Cyclic amine phenyl beta-3 adrenergic receptor agonists

ABSTRACT

This invention provides compounds of Formula I having the structure  
                 
 
     wherein,  
     R 1 , R 2 , R 3 , R 4 , R 5 , T, T 1 , T 2 , and X are as defined hereinbefore, or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, glaucoma, ocular hypertension and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/218,627, filed Jul. 17, 2000.

BACKGROUND OF THE INVENTION

[0002] This invention relates to cyclic amine phenyl β₃ adrenergicreceptor agonists useful for the treatment of metabolic disordersrelated to insulin resistance or hyperglycemia (typically associatedwith obesity or glucose intolerance), atherosclerosis, gastrointestinaldisorders, neurogenetic inflammation, glaucoma, ocular hypertension, andfrequent urination; and are particularly useful in the treatment orinhibition of type II diabetes.

[0003] The subdivision of β adrenergic receptors (β-AR) into β₁- andβ₂-AR has led to the development of β₁- and β₂-antagonists and/oragonists which have been useful for the treatment of cardiovasculardisease and asthma. The recent discovery of “atypical” receptors, latercalled β₃-AR, has led to the development of β₃-AR agnoists which may bepotentially useful as antiobesity and antidiabetic agents. For recentreviews on β₃-AR agnoists, see: 1. A. D. Strosberg, Annu. Rev. PharmacolToxicol. 1997, 37, 421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33,193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C.Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25,11.

[0004] Compounds that are potent and selective β₃ agonists, may bepotentially useful antiobesity agents. Low levels or lack of β₁ andβ₂-agonistic properties will minimize or eliminate the adverse sideeffects that are associated with β₁ and β₂ agonistic activities, i.e.increased heart rate, and muscle tremor, respectively. Earlydevelopments in the β₃-agonist field are described in European patent427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, and 5,153,210.These early patents purport to claim compounds with greater selectivityfor the β₃-AR than for the β₁- and β₂-AR's. However, clinical trials inhumans with such compounds have not been successful to date.

[0005] More recently, potent and selective human β₃ agonists have beendescribed in several patents and published applications: WO 98/32753, WO97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO95/29159, European Patents 659737, 801060, 714883, 764640, 827746, andU.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. Thesecompounds were evaluated in Chinese hamster ovary (CHO) cells testprocedures which predicts the effects that can be expected in humans.These assays utilize cloned human β3 receptors, expressed in CHO cells(see refs. Granneman et al., Mol Pharmacol., 1992, 42, 964; Emorine etal., Science, 1989, 245, 1118; Liggett Mol. Pharmacol., 1992, 42, 634).

[0006] β₃-Adrenergic agonists also are useful in controlling thefrequent urge of urination. It has been known that relaxation of thebladder detrusor is under beta adrenergic control (Li J, Yasay G and KauS. Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinarybladder. Pharmacology 1992; 44: 13-18). Recently, a number oflaboratories have provided experimental evidence in a number of animalspecies including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, etal. Species differences in the distribution of the beta-adrenoceptorsubtypes in bladder smooth muscle. Br. J. Pharmacol. 1998; 124: 593-599)that activation of the β₃ receptor subtype by norepinephrine isresponsible for relaxation of the urinary bladder. Urge urinaryincontinence is characterized by abnormal spontaneous bladdercontractions that can be unrelated to bladder urine volume. Urge urinaryincontinence is often referred to hyperactive or unstable bladder.Several etiologies exist and fall into two major categories, myogenicand neurogenic. The myogenic bladder is usually associated with detrusorhypertrophy secondary to bladder outlet obstruction, or with chronicurinary tract infection. Neurogenic bladders are associated with anuninhibited micturition reflex. An upper motor neuron disease is usuallythe underlying cause. In either case, the disease is characterized byabnormal spontaneous contractions that result in an abnormal sense ofurinary urgency and involuntary urine loss. At present, the most commontherapy for hyperactive bladder includes the use of antimuscarinicagents to block the action of the excitatory neurotransmitteracetylcholine. While effective in neurogenic bladders, their utility inmyogenic bladders is questionable. In addition, due to severe dry mouthside-effects associated with antimuscarinic therapy, the patientcompliance with these agents is only approximately 30%.

[0007] In the bladder, β₃ adrenergic receptor agonists activate adenylylcyclase and generate cAMP through the G-protein coupled β₃ receptor. Theresulting phosphorylation of phospholamban/calcium ATPase enhancesuptake of calcium into the sarcoplasmic reticulum. The decrease inintracellular calcium inhibits bladder smooth muscle contractility.

[0008] It is suggested therefore, that activation of the β₃ adrenergicreceptor in the urinary bladder will inhibit abnormal spontaneousbladder contractions and be useful for the treatment of bladderhyperactivity. Note, that unlike the antimuscarinics, β₃ adrenergicreceptor agonists would be expected to be active against both neurogenicand myogenic etiologies.

[0009] Despite all these recent developments there is still no singletherapy available for the treatment of type II diabetes (NIDDM),obesity, atherosclerosis, gastrointestinal disorders, neurogeneticinflammation, frequent urination and related diseases. A potent andselective β₃ adrenergic receptor agonist is therefore highly desirablefor the potential treatment of such disease states.

DESCRIPTION OF THE INVENTION

[0010] This invention provides compounds of Formula I having thestructure

[0011] wherein

[0012] A is Ar or Het;

[0013] X is —OCH₂—, —SCH₂—, or a bond;

[0014] T¹ is (CH₂)_(m);

[0015] T² is (CH₂)_(n);

[0016] T is a bond, alkyl of 1-6 carbon atoms optionally substitutedwith R¹¹, alkenyl of 2-7 carbon atoms optionally substituted with R¹¹,alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, alkylaminoof 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety,alkylthioalkyl of 1-6 carbon atoms per alkyl moiety, alkoxy of 1-6carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl moiety,alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7 carbonatoms, or alkenylcarbonyl of 3-8 carbon atoms;

[0017] R¹, R², and R³ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy,propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino,dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group,dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbon atoms, or Aroptionally substituted with R¹¹;

[0018] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, halogen, hydroxy,alkyoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, amino,alkylamino of 1-6 carbon atoms, carboxy, acyl of 2-7 carbon atoms,ArCO—, alkoxycarbonyl of 2-7 carbon atoms, aminocarbonyl,alkylaminocarbonyl of 2-7 carbon atoms, alkylsulfonyl of 1-6 carbonatoms, or alkylsulfonylamino of 1-6 carbon atoms,

[0019] R⁵ is

[0020] Aa is (i) an amino acid, wherein the nitrogen of amino acidattached to the adjacent carbonyl of R⁵; or (ii) an alkyl ester of anamino acid, wherein the nitrogen of amino acid attached to the adjacentcarbonyl of R⁵, and the alkyl moiety of the alkyl ester contains 1-6carbon atoms;

[0021] Y and Z are each, independently, NR⁷, O, or S;

[0022] X¹ and X² are each, independently, CO or SO₂; a dotted linerepresents and optional double bond; of

[0023] R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³, or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹;

[0024] R⁹ and R¹⁰ are each, independently, alkyl optionally substitutedby R¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted byR¹⁵; Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionallymono-, di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵;

[0025] R¹¹, R¹², or R¹³ are each, independently, alkyl of 1-6 carbonatoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atomsin the alkyl moiety, Ar optionally substituted with R¹⁴, Het optionallysubstituted with R¹⁴, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo,—CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkyl moiety has 1-6carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkylof 1-6 carbon atoms, —NHSO₂-alkyl of 1-6 carbon atoms, —NHSO₂—Ar, or—NHSO₂—Het; or when R¹¹ and R¹² are contained on a common carbon atom ofan alkyl moiety, they may be taken together to form a spiro cycloalkylring of 3-8 carbon atoms;

[0026] R¹⁴ is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,hydroxy, acyl of 2-7 carbon atoms, —SO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbonatoms;

[0027] R¹⁵ is

[0028] (a) hydroxy, halogen; —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶,triflouromethyl, alkyl of 1-6 carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷wherein the alkyl moiety contains 1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷,—NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or —NR¹⁶CO₂R¹⁶; or

[0029] (b) alkyl of 1-6 carbon atoms mono-, or di-substituted withhydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl; alkylof 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷; —COR¹⁷;—NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;

[0030] (c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; or

[0031] (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen;

[0032] R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties maybe optionally mono-, di-, or tri-substituted with halogen, nitro,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H, —CO₂alkyl of 1-6carbon atoms, or —SO₂alkyl of 1-6 carbon atoms;

[0033] R¹⁷ is R¹⁶ or —NR¹⁶R¹⁶;

[0034] Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms,having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;wherein the heterocycle may be saturated, unsaturated, or partiallyunsaturated; and may be optionally fused to a phenyl ring;

[0035] Ar is an aromatic ring system containing 1-2 carbocyclic aromaticrings having 6-10 carbon atoms;

[0036] m=1-3;

[0037] n=1-3;

[0038] or a pharmaceutically acceptable salt thereof, which areselective agonists at human β₃ adrenergic receptors and are useful intreating or inhibiting metabolic disorders related to insulin resistanceor hyperglycemia (typically associated with obesity or glucoseintolerance), atherosclerosis, gastrointestinal disorders, neurogeneticinflammation, glaucoma, ocular hypertension, and frequent urination; andare particularly useful in the treatment or inhibition of type IIdiabetes.

[0039] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, such as alkali metal salts (for example,sodium, lithium, or potassium), alkaline earth metal salts, ammoniumsalts, alkylammonium salts containing 1-6 carbon atoms ordialkylammonium salts containing 1-6 carbon atoms in each alkyl group,and trialkylammonium salts containing 1-6 carbon atoms in each alkylgroup, when a compound of this invention contains an acidic moiety.

[0040] The compounds of the instant invention all contain at least oneasymmetric center. Additional asymmetric centers may be present on themolecule depending upon the nature of the various substituents on themolecule. Each such asymmetric center will produce two optical isomersand all such optical isomers, as separated, pure or partially purifiedoptical isomers or racemic mixtures thereof, are included within thescope of the instant invention. Any enantiomer of a compound of thegeneral Formula I may be obtained by stereospecific synthesis usingoptically pure starting materials of know configuration.

[0041] The compounds of the present invention may also contain geometricisomers. Thus, the present invention includes all individual isomers andmixtures thereof.

[0042] Alkyl, alkenyl, and alkynyl include both straight chain as wellas branched moieties. Halogen means bromine, chlorine, fluorine, andiodine. Where a substituent contains one or more moieties which have thesame designation, each of the moieties can be the same or different. Arand the term “aryl” includes monocyclic or bicyclic aromatic carbocyclicgroups such as phenyl and naphthyl. Benzyl is the preferred arylalkylmoiety.

[0043] Preferred Het moieties include: (a) 6-membered saturated,partially unsaturated, or unsaturated heterocycles containing 1-2nitrogens, optionally fused to a phenyl ring; (b) 5-membered saturated,partially saturated, or unsaturated heterocycles containing 1-3nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl ring;(c) saturated, partially unsaturated, or unsaturated bicyclicheterocycles containing 1-4 nitrogen, oxygen, or sulfur atoms; (d)carbazole, dibenzofuran, and dibenzothiophene. In the Het of categories(a), (b), and (c), ring carbon atoms may be carbonyl moieties, where thering does not contain a double bond in that position (for example,thiazolidine-2,4-dione).

[0044] More preferred Het rings include pyrrole, furan, thiophene,imidazole, pyrazole, furazan, triazole, tetrazole, oxazole, oxadiazole,isoxazole, thiazole, isothiazole, thiadiazole, pyridine, pyrimidine,pyridazine, pyrazine, 1,3,5-triazine, 1,2,4,5-tetrazine, benzofuran,isobenzofuran, indole, isoindole, benzothiophene, benzimidazol,3H-benzoxazol-2-one, benzotriazole, quinoline, isoquinoline,quinazoline, indazole, 1H-quinolin-2-one, 3,4-dihydro-1H-quinolin-2-one,2,3-dihydro-1H-indole, 1,3-dihydro-benzoinimidazol-2-thione, carbazole,3,5-dioxo-[1,2,4]oxadiazolidine, 2,4-dioxo-3-thiazolidine,1H-benzoimidazole, 2-thioxo-thiazolidin-4-one,2-imino-4-oxo-thiazolidine, 2-oxo-1,2,3,4-tetrahydro-quinoline,2,4-dioxo-thiazolidine, 5-oxo-2,5-dihydro-1H-pyrazole,2-oxo-2,3-dihydro-1H-benzimidazole, 9H-carbazole, benzothiophene,morpholine, piperidine, and 1,3-benzodioxole. It is understood that Hetdo not contain heteroatoms in arrangements which would make theminherently unstable. For example, the term Het does not include ringsystems containing O—O bonds in the ring backbone.

[0045] Preferred amino acids include alanine, valine, leucine,isoleucine, proline, phenylalanine, tryptophan, methionine, glycine,serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparticacid, glutamic acid, lysine, arginine, histidine, β-alanine,cyclopropane amino acids (such as 1-aminocyclopropane-1-carboxylic acid,allo-coronamic acid and 2,3-methanohomoserine),1-aminocyclohexane-1-carboxylic acid, isonipecotic acid,2-azetidinecarboxylic acid, and esters thereof.

[0046] Preferred compounds of Formula I are those in which

[0047] A is Ar or Het;

[0048] X is —OCH₂— or a bond;

[0049] T¹ is (CH₂)_(m);

[0050] T² is (CH₂)_(n);

[0051] T is a bond, alkyl of 1-6 carbon atoms optionally substitutedwith R¹¹, alkenyl of 2-7 carbon atoms optionally substituted with R¹¹,or alkoxyalkyl of 1-6 carbon atoms per alkyl moiety;

[0052] R¹, R², and R³ are each, independently, hydrogen, alkyl of 1-6carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbonatoms, benzyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, acylamino of 2-7 carbon atoms,alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino, —CO₂-alkyl of1-6 carbon atoms, or Ar optionally substituted with R¹¹;

[0053] R⁴ is hydrogen or halogen;

[0054] R⁵ is

[0055] Aa is (i) an amino acid, wherein the nitrogen of amino acidattached to the adjacent carbonyl of R⁵; or (ii) an alkyl ester of anamino acid, wherein the nitrogen of amino acid attached to the adjacentcarbonyl of R⁵, and the alkyl moiety of the alkyl ester contains 1-6carbon atoms;

[0056] Y and Z are each, independently, NR⁷, O, or S;

[0057] X¹ and X² are each, independently, CO or SO₂;

[0058] a dotted line represents and optional double bond;

[0059] R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; cycloalkyl of3-8 carbon atoms optionally substituted by R¹¹, R¹², and R¹³;bicycloalkyl of 7-11 carbon atoms optionally substituted by R¹¹, R¹²,and R¹³; —CO₂-alkyl of 1-6 carbon atoms; Het optionally substituted byR¹¹, R¹², or R¹³; or Ar optionally substituted by R¹¹, R¹², and R¹³; orwhen R⁶ and R⁷ are contained on a common nitrogen, they may be takentogether to form a saturated 5-7 membered heterocycle that is optionallysubstituted with R¹¹;

[0060] R⁹ and R¹⁰ are each, independently, alkyl optionally substitutedby by R¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted byR¹⁵; Het optionally mono-, di-, or tri-substituted by R¹⁵;

[0061] R¹¹, R¹², or R¹³ are each, independently, alkyl of 1-6 carbonatoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atomsin the alkyl moiety, Ar optionally substituted with R¹⁴, Het optionallysubstituted with R¹⁴, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo,—CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkyl moiety has 1-6carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkylof 1-6 carbon atoms, —NHSO₂-alkyl of 1-6 carbon atoms, —NHSO₂—Ar, or—NHSO₂—Het; or when R¹¹ and R¹² are contained on a common carbon atom ofan alkyl moiety, they may be taken together to form a spiro cycloalkylring of 3-8 carbon atoms;

[0062] R¹⁴ is halogen, alkoxy of 1-6 carbon atoms, alkyl of 1,6 carbonatoms, hydroxy, acyl of 2-7 carbon atoms, —SO₂-alkyl of 1-6 carbonatoms, —CO₂-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13carbon atoms;

[0063] R¹⁵ is

[0064] (a) halogen, —CN, —OR¹⁶, triflouromethyl, alkyl of 1-6 carbonatoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains atoms,—CO₂R¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷; or

[0065] (b) alkyl of 1-6 carbon atoms mono-, or di-substituted withhalogen; —NR¹⁶COR¹⁷; Ar which may be optionally mono- or di-substitutedby R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may be optionallymono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;

[0066] (c) Het optionally mono- or di-substituted by R¹⁶; —OR¹⁶,—NR¹⁶R¹⁶, or halogen; or

[0067] (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen;

[0068] R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of4-14 carbon atoms, benzyl, Ar or Het, wherein the Ar or Het moieties maybe optionally mono-, di-, or tri-substituted with halogen, nitro,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, trifluoromethyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H, —CO₂alkyl of 1-6carbon atoms, or —SO₂alkyl of 1-6 carbon atoms;

[0069] R¹⁷ is R¹⁶ or —NR¹⁶R¹⁶;

[0070] Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms,having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;wherein the heterocycle may be saturated, unsaturated, or partiallyunsaturated; and may be optionally fused to a phenyl ring;

[0071] Ar is an aromatic ring system containing 1-2 carbocyclic aromaticrings having 6-10 carbon atoms;

[0072] m=1-2;

[0073] n=1-2;

[0074] or a pharmaceutically acceptable salt thereof.

[0075] Specifically preferred compounds of this invention are:

[0076] a)N-[5-((1R)-2-{1-[4-(3,5-dioxo-[1,2,4]oxadiazolidin-2-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0077] b)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid tert-butyl-ester;

[0078] c)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid;

[0079] d)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid ethyl-ester;

[0080] e)5-(3-fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0081] f)5-(3-bromo-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;

[0082] g)5-(3-fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;

[0083] h)N-[5-(2-{1-[2-bromo-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0084] i)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0085] j)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-thioxo-thiazolidin-4-one;

[0086] k)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzyl}-thiazolidin-2,4dione;

[0087] l)5(4-{4-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidin-1-}-benzyl)-thiazolidine-2,4-dione;

[0088] m)5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;

[0089] n)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;

[0090] o)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0091] p)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0092] q)5-(4-{4-[2-(3-chloro-phenyl)-(2R)-2-hydroxyethylamino}-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0093] r)5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0094] s)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0095] t)5(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-thioxo-thiazolidin-4-one;

[0096] u)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazolidine-2,4-dione;

[0097] v)N-[5-((2R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0098] w)N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0099] x)5-(4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-imidazolidine-2,4-dione-piperidin-1-yl}-benzyl)-imidazolidine-2,4-dione;

[0100] y)N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

[0101] z)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

[0102] aa)4-((2S)-2-hydroxy-3-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;

[0103] bb)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

[0104] cc)5-(4-{4-[(2S)-2-hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0105] dd)N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide;

[0106] ee)N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide;

[0107] ff) (R)-propane-2-sulfonic acid[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide;

[0108] gg)N-[2-chloro-5-((1R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;

[0109] hh)N-(5-{(1R)-2-[(1-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidin-4-yl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)benzenesulfonamide;

[0110] ii)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

[0111] jj) ethyl[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]acetate;

[0112] kk)[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]aceticacid;

[0113] ll)[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2H-tetraazol-2-yl]aceticacid;

[0114] mm)5-{4-[4-({(2S)-2-hydroxy-2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethyl}amino)piperidine-1-yl]benzyl}-1,3-thiazolidine-2,4-dione;

[0115] nn)5-{4-[4-({(2S)-2-[3-(3,4-dichlorophenyl)isoxazol-5-yl]-2-hydroxyethyl}amino)piperidin-1-yl}benzyl}-1,3-thiazole-2,4-dione;

[0116] oo)N-(4-{(1R)-2-[(1-(4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}peridine-4yl)amino]-1-hydroxyethyl)}phenyl)methanesulfonamide;

[0117] pp)5-[4-(4-{[4-(2S)-2-(3-bromoisoxazol-5-yl)-2-hydroxyethyl]amino}piperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione;

[0118] qq)5-(4-{4-[(2S)-2-hydroxy-3-(pyridin-3-yloxy)-propylamino]piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0119] rr)5-(4-{4-[(2S)-2-hydroxy-3-(6-methyl-pyridin-3-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;

[0120] ss) 5-{4-[4-((2S)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione;

[0121] tt)5-(4-{4-[(2S)-2-(6-amino-pyridin-3-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dionehydrochloride;

[0122] uu)5-{4-[4-((2R)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione;

[0123] vv)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-pyridin-2-yl]-methanesulfonamide;

[0124] ww)5-(3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-2-fluoro-phenyl]-piperidin-4-ylamino}-(2S)-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylicacid ethyl ester;

[0125] xx)N-[(2R)-2-hydroxy-5-(1-hydroxy-2-{1-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

[0126] yy)4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzoicacid ethyl ester;

[0127] zz){4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester;

[0128] aaa){4-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester hydrochloride;

[0129] bbb)(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-aceticacid;

[0130] ccc)3-(4-{4-[(2R)-2-hydroxy2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid ethyl ester;

[0131] ddd)3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-propionicacid;

[0132] eee)(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzyloxy)-aceticacid;

[0133] fff)4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid;

[0134] ggg)3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-propionicacid ethyl ester;

[0135] hhh)2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-malonicacid diethyl ester;

[0136] iii)2-(4-{4-[(2R)2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-malonicacid monoethyl ester;

[0137] jjj)4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzamide;

[0138] kkk)N-benzyloxy-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzamide;

[0139] lll) diethyl(2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioate;

[0140] mmm) ethyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]propanoate;

[0141] nnn)(2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioicacid;

[0142] ooo)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)-beta-alanine;

[0143] ppp) ethyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate;

[0144] qqq)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidin}benzoyl)amino]aceticacid;

[0145] rrr)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid ethyl ester;

[0146] sss)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid;

[0147] ttt)1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid methyl ester;

[0148] uuu)1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid;

[0149] vvv)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid ethyl ester;

[0150] www)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid;

[0151] xxx)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid methyl ester;

[0152] yyy)(2S)-2-(4-}4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid;

[0153] zzz) methyl1-[(4-{4-[((2R)-2-hydroxy-2-}4-hydroxy-3-piperidinyl}benzoyl)amino]cyclopropanecarboxylate;

[0154] aaaa)[butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-amino]-aceticacid ethyl ester;

[0155] bbbb) methyl[(4-{4-[((2R)-2-hydroxy-2-}4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate;

[0156] cccc)(2S)-2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid methyl ester;

[0157] dddd)(2E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid;

[0158] eeee)4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzamide;

[0159] ffff)4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-sulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-l}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-oxoazepanyl]benzamide;

[0160] gggg)N-butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-(1H-tetraazol-5-ylmethyl)benzamide.

[0161] hhhh)N-{4-[4-(2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-phenyl}-4-methoxy-benzenesulfonamide;

[0162] iiii)N-(4-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-4-methoxy-benzenesulfonamide;

[0163] jjjj)N-[4-(4-{4-[2hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-phenylsulfamoyl)-phenyl]-acetamide;

[0164] kkkk)N-(4-{4-[4-((2R)-2-hydroxy-2-phenyl-ethylamino)-peridin-1-yl]-phenylsulfamoyl}-phenyl)-acetamide;

[0165] llll )N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0166] mmmm)N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;

[0167] nnnn)N-[4-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;

[0168] oooo)N-(4-{[4-(4-{[2-hydroxy-3-(4-methoxyphenoxy)propyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0169] pppp)N-(4-{[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl]phenyl)acetamide;

[0170] qqqq)N-(4-{[2-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0171] rrrr)N-(4-{[2-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0172] ssss)N-[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;

[0173] tttt)N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0174] uuuu)N-(4-{[4-(4-{[2-(2,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0175] vvvv)N-(4-{[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0176] wwww)N-{4-[(4-{4-[(2-hydroxy-2-}4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide;

[0177] xxxx)4-{[(hexylamino)carbonyl]amino}-N-[4-(4-{[2-hydroxy-2-(6-methyl-3-pyridinyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0178] yyyy)N-(4-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0179] zzzz)5-[2-({1-[4-({[4-(acetylamino)phenyl]sulfonyl}amino)phenyl]-4-piperidinyl}amino)-1-hydroxyethyl]-1H-indole-7-carboxamide;

[0180] aaaaa)N-[4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide;

[0181] bbbbb)4-{[(hexylamino)carbonyl]amino{-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0182] ccccc)4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;

[0183] ddddd)4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-{4-[4-({2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0184] eeeee)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamide;

[0185] fffff)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0186] ggggg)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-piperidinyl}phenyl)-3,4-dimethoxybenzenesulfonamide;

[0187] hhhhh)4-butoxy-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;

[0188] iiiii)N-(4-{[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;

[0189] jjjjj)5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3-methyl-1-benzothiophene-2-sulfonamide;

[0190] kkkkk)4-cyano-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0191] llll)4-cyano-N-[(4-cyanophenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0192] mmmmm)3-bromo-5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide;

[0193] nnnnn)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-5-(3-isoxazolyl)-2-thiophenesulfonamide;

[0194] ooooo)4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1-H-tetraazol-1-yl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;

[0195] ppppp)4-butoxy-N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0196] qqqqq)N-[4-(4-{[3-(9H-carbazol-4-yloxy)-(2S)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-4-{[(hexylamino)carbonyl]amino}benzenesulfonamide;

[0197] rrrrr)N-{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide;

[0198] sssss)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0199] ttttt)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide;

[0200] uuuuu)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-5-(2-pyridinyl)-2-thiophenesulfonamide;

[0201] vvvvv)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide;

[0202] wwwww)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide;

[0203] xxxxx)N-(4-{4[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-octanesulfonamide;

[0204] yyyyy)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-octanesulfonamide;

[0205] zzzzz)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;

[0206] aaaaaa)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;

[0207] bbbbbb)4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0208] cccccc)4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;

[0209] dddddd)N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide;

[0210] eeeeee)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-1-octanesulfonamide;

[0211] ffffff)4-{[(hexylamino)carbonyl]amino}-N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0212] gggggg)N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide;

[0213] hhhhhh)N-[4-({4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide;

[0214] iiiiii)N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}phenyl)-,4-dimethoxybenzenesulfonamide;

[0215] jjjjjj)N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino-1-piperidinyl}phenyl)-1-butanesulfonamide;

[0216] kkkkkk)4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;

[0217] lllll)N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-{[(hexylamino)carbonyl]amino}benzenesulfonamide;

[0218] mmmmmm) ethyl{4-[(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetate;

[0219] nnnnnn) methyl{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenoxy}acetate;

[0220] oooooo) methyl[4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenoxy]acetate;

[0221] pppppp)N-[5-({(2S)-3-[(1-{4-[(butylsulfonyl)amino]phenyl}-4-piperidinyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]benzenesulfonamide;

[0222] qqqqqq)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(isopropylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide;

[0223] rrrrrr)4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]benzoicacid;

[0224] ssssss) ethyl4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]benzoate;

[0225] tttttt) methyl{4-[(4-{4-[((2R)-2-{4-chloro-3-[(methylsulfonyl)amino]phenyl}-2-hydroxyethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenoxy}acetate;

[0226] uuuuuu) methyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylate;

[0227] vvvvvv)3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylicacid;

[0228] wwwwww) benzyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]acetate;

[0229] xxxxxx)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid;

[0230] yyyyyy) benzyl[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]acetate;

[0231] zzzzzz)[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid;

[0232] aaaaaaa)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3-pyridinesulfonamide;

[0233] bbbbbbb)3,4-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0234] ccccccc)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide;

[0235] ddddddd)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-4-(trifluoromethoxy)benzenesulfonamide;

[0236] eeeeeee)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-4-methoxybenzenesulfonamide;

[0237] fffffff)4-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0238] ggggggg)4-butyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0239] hhhhhhhh)3,5-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1-H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0240] iiiiiii)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2,5-dimethoxybenzenesulfonamide;

[0241] jjjjjjj)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2,5-dimethoxybenzenesulfonamide;

[0242] kkkkkkk) ethyl{[(4-butylphenyl)sulfonyl]-4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}acetate;

[0243] lllllll)5bromo-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide;

[0244] mmmmmmm)5-bromo-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide;

[0245] nnnnnnn) ethyl([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;

[0246] ooooooo) ethyl5-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-1H-indole-3-carboxylate;

[0247] pppppp) ethyl4-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate;

[0248] qqqqqqq) benzyl((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;

[0249] rrrrrrr)((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid;

[0250] sssssss)([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid;

[0251] ttttttt) ethyl((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;

[0252] uuuuuuu)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0253] vvvvvv)N-{[5-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)-2-thienyl]methyl}benzamide;

[0254] wwwwwww)N-[(5-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;

[0255] xxxxxxx)N-[(5-{[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;

[0256] yyyyyyy)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1-H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0257] zzzzzzz)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0258] aaaaaaaa)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0259] bbbbbbbb)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0260] cccccccc)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0261] dddddddd)N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]-2-thiophenesulfonamide;

[0262] eeeeeeee)4-butoxy-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;

[0263] ffffffff)N-[4-(4-{[(2S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]-2-thiophenesulfonamide;

[0264] gggggggg)4-butoxy-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;

[0265] hhhhhhhh)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide;

[0266] iiiiiiii)N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0267] jjjjjjjj)N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0268] kkkkkkkk)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide;

[0269] llllllll) ethyl3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate;

[0270] mmmmmmmm)3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid;

[0271] nnnnnnnn) ethyl3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate;

[0272] ooooooo)3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid;

[0273] pppppppp) ethyl3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate;

[0274] qqqqqqqq)3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid;

[0275] rrrrrrrr) ethyl{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate;

[0276] ssssssss){[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}aceticacid;

[0277] tttttttt) ethyl{[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate;

[0278] uuuuuuuu){[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}aceticacid;

[0279] vvvvvvvv)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzamide;

[0280] wwwwwwww)2-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide;

[0281] xxxxxxxx)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-(4-morpholinyl)acetamide;

[0282] yyyyyyyy)2-(dimethylamino)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide;

[0283] zzzzzzzz)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-dimethoxybenzamide;

[0284] aaaaaaaaa)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}butanamide;

[0285] bbbbbbbbb)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]butanamide;

[0286] ccccccccc)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzamide;

[0287] ddddddddd)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzamide;

[0288] eeeeeeeee)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1,3-benzodioxole-5-carboxamide;

[0289] fffffffff)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl}-1,3-benzodioxole-5-carboxamide;

[0290] ggggggggg)3-cyclopentyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}propanamide;

[0291] hhhhhhhhh)3-cyclopentyl-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)propanamide;

[0292] iiiiiiiii)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1,3-benzodioxole-5-carboxamide;

[0293] jjjjjjjjj)N-acetyl-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]acetamide;

[0294] kkkkkkkkk)4-butoxy-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;

[0295] lllllllll)N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0296] mmmmmmmmmm)N-(4-{[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide;

[0297] nnnnnnnnn)4-butoxy-N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;

[0298] ooooooooo)N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]acetamide;

[0299] ppppppppp)N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;

[0300] qqqqqqqqq)N-(4-{[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide

[0301] or a pharmaceutically acceptable salt thereof.

[0302] The compounds of this invention can be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using literature procedures.These schemes show the preparation of representative compounds of thisinvention.

[0303] According to one route (Scheme 1),1,4-dioxa-8-azaspiro[4.5]decane is reacted with 4-fluorobenzaldehyde 1in the presence of base such as pyridine or potassium carbonate toafford aldehyde 2. This reaction can be carried out in a polar solventsuch as anhydrous acetonitrile, acetone, N,N-dimethylformamide, orpyridine. Compound 4 is obtained via a Knoevenagel condensation betweenan appropriate cyclic lactam 3 and the aldehyde 2. In this reactionsodium acetate, β-alanine, glycine, pyridine, piperidine, pyrrolidine,sodium methoxide, potassium acetate, sodium carbonate and the like canbe used as a base, and an alcohol such as methanol, ethanol,isopropanol, methoxyethanol and the like, N,N-dimethylformamide, water,acetic acid and the like can be used as a solvent. Ketal hydrolysis isaccomplished in the presence of strong acid such as concentratedhydrochloric acid or 10-30% sulfuric acid. The desired final product 7,wherein A, R₁, R₂, R₃, R₄, R₆, X, Y and Z are as defined above, isprepared by utilizing reductive amination of piperidione 5 withappropriate arylethanolamines or aryloxypropanolamines 6, many of whichare comercially available or can be readily prepared as described inScheme 19 and Scheme 20. The reductive amination can be carried out, forexample, with hydrogen and catalytic palladium, or with sodiumborohydride, sodium triacetoxyborohydride and the like in a polarsolvent such as methanol, N,N-dimethylformamide and the like. The finalproducts can be purified by recrystallization, trituration, preparativethin layer chromatography, flash column chromatography on silica gel, orhigh performance liquid chromatography. Purification of intermediatescan be achieved in the same manner. A salt is optionally produced by theaddition of an acid or base, such as hydrogen chloride gas orhydrochloric acid.

[0304] In some cases the C—C double bond of compound 4 can be reduced(Scheme 2) by catalytic hydrogenation in the presence of a metalcatalyst such as palladium, platinum, rhodium and the like. An alcoholsuch as methanol, ethanol, isopropanol and the like, acetic acid,tetrahydrofuran (THF), dioxane and the like can be used as a solvent inthe hydrogenation. In other cases, owing to the presence of sulfur inthe molecule, the C—C double bond of compound 4 can not be reduced byordinary catalytic hydrogenation. However, the reduction can be achievedby a hydrogen transfer reaction using 3-10% sodium mercury amalgam,zinc, dihydropyridine, tin and the like as a hydrogen donor. In thisreaction THF/water, acetic acid, toluene, ethanolic hydrogen iodide andthe like can be used as a solvent. Ketal hydrolysis under acidicconditions followed by reductive amination, as previously described inScheme 1, furnishes the desired final product 10, wherein A, R₁, R₂, R₃,R₄, X, Y and Z are as defined above (Scheme 2). A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid.

[0305] Compound 9 could be optionally alkylated with an appropriatealkylating agents R₆-halo in the presence of base to give the alkylatedcompound 11 (Scheme 2). At this time, bases to be used include cesiumcarbonate, potassium carbonate, sodium carbonate, sodium acetate,potassium acetate and the like. Solvents used includeN,N-dimethylformamide, acetone, acetonitrile and the like. A reductiveamination between ketone 11 and amine 6, as previously described inScheme 1, furnishes the final product 12, wherein A, R₁, R₂, R₃, R₄, R₆,X, Y and Z are as defined above. A salt is optionally produced by theaddition of an acid or base, such as hydrogen chloride gas orhydrochloric acid.

[0306] The compound represented by the above formula I wherein R₅ istetrazole can be prepared by one of the following synthetic schemes(Scheme 3 & Scheme 4). Nitrile compound 14 can be obtained by condensing1,4-dioxa-8-azaspiro[4.5]decane with 4-fluorobenzonitrile as previouslydescribed in Scheme 1. The reaction for the formation of the tetrazolescan be carried out by reacting nitrites 14 with sodium azide,tributyltin azide and the like in the presence of an amine salt such asammonium chloride, triethylamine hydrochloride, diethylaminehydrochloride, tripropylamine hydrosulfate and the like. Solvents usedin this reaction include aromatic hydrocarbons such as toluene, xylene,benzene, nitrobenzene and the like. Sometimes the cycloaddition can alsobe performed in a polar solvent such as N,N-dimethylformamide,dimethylsulfoxide and the like. Ketal hydrolysis under acidic conditionsfollowed by reductive amination, as previously described in Scheme 1,furnishes the final product 17 (Scheme 3), wherein A, R₁, R₂, R₃, R₄ andX are as defined above. A salt is optionally produced by the addition ofan acid or base, such as hydrogen chloride gas or hydrochloric acid.

[0307] Tetrazole 15 could be optionally alkylated with an appropriatealkylating agents R₆-halo in the presence of base such as cesiumcarbonate to give a pair of isomers (18 & 19) which could be separatedby flash column chromatography on silica gel. Ketal hydrolysis underacidic conditions followed by reductive amination, as previouslydescribed in Scheme 1, furnishes the final products 22 or 23, wherein A,R₁, R₂, R₃, R₄, R₆ and X are as defined above. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid.

[0308] The compound represented by the above formula I wherein R₅ isoxadiazolidine can be prepared by the following synthetic scheme (Scheme5). Compound 24 is obtained by a reductive amination reaction betweenaldehyde 2 and hydroxylamine. This reductive amination can be carriedout essentially under the same conditions as that previously describedin Scheme 1. N-Hydroxyurea 25 is obtained by reacting compound 24 withisocyanate such as chlorocarbonyl isocanate, trimethylsilyl isocyanateand the like, followed by ketal hydrolysis. In the isocyanate reaction apolar solvent such as 1,4-dioxane, tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide and the like can be used as asolvent. Ketal hydrolysis is conveniently conducted under acidicconditions as that previously described in Scheme 1. The oxadiazolidinering is formed by reacting the N-hydroxyurea 25 with chloroformate suchas methyl chloroformate, ethyl chloroformate, isobutyl chloroformate andthe like in the presence of strong base such as sodium hydride,potassium hydroxide and the like. The final product 27, wherein A, R₁,R₂, R₃, R₄ and X are as defined above, is obtained by reductiveamination between ketone 26 and amine 6 using basically the sameconditions as previously described in Scheme 1. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid.

[0309] The compound represented by the above formula I wherein R₅ ispyrazole can be prepared by the following synthetic scheme (Scheme 6).Pyrazole compound 29 can be obtained by condensing1,4-dioxa-8-azaspiro[4.5]decane with 4-fluorobenzonate 28 as previouslydescribed in Scheme 1, followed by pyrazole ring formation which can becarried out by reacting with hydrazine. Solvents used in this ringformation include methanol, ethanol, tetrahydrofuran and the like. Ketalhydrolysis under acidic conditions followed by reductive amination, aspreviously described in Scheme 1, furnishes the final product 31,wherein A, R₁, R₂, R₃, R₄ and X are as defined above. A salt isoptionally produced by the addition of an acid or base, such as hydrogenchloride gas or hydrochloric acid.

[0310] The compound represented by the above formula I wherein R₅ isacid or ester can be prepared by the following synthetic scheme (Scheme7). According to one route, 1,4-dioxa-8-azaspiro[4.5]decane is reactedwith 4-fluorobenzoate 32 in the presence of base such as pyridine orpotassium carbonate to afford ester 33. This reaction can be carried outin a polar solvent such as anhydrous acetonitrile, acetone,dimethylformamide, or pyridine. Acid 35 is obtained via a basichydrolysis of ester 33. In this reaction lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like can be used as a base, andwater or a mixture of water with methanol, ethanol, dioxane and the likecan be used as a solvent. Ketal 35 hydrolysis is accomplished in thepresence of strong acid such as concentrated hydrochloric acid or 10-30%sulfuric acid. The desired final product (acid 37), wherein A, R₁, R₂,R₃, R₄ and X are as defined above, is prepared by utilizing reductiveamination of piperidiones 36 with appropriate arylethanolamines oraryloxypropanolamines 6, as previously described in Scheme 1. Thecorresponding ester 38, wherein A, R₁, R₂, R₃, R₄, R₆ and X are asdefined above (provided that in 38 R₆ can not be hydrogen), could besynthesized in the same manner starting with the ester 33 by ketalhydrolysis followed by reductive amination sequence. A salt isoptionally produced by the addition of an acid or base, such as hydrogenchloride gas or hydrochloric acid.

[0311] Mono peptide derived from the acid 36 and amino acid and itsester thereof, can be prepared by, for example, the following syntheticscheme(Scheme 8). The carboxylic acid 36 is coupled to the aminenitrogen of amino acid (ester), wherein the amino acid (ester) means thecarboxylic acid functionality of the amino acid was protected as anester. In this amide bond formation process1,3-dicyclohexylcarbodiimide,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide,diisopropylcarbodiimide, 1,1′-carbonyldiimidazole,6-chloro-2,4-dimethoxy-1,3,5-triazine and the like can be used as acoupling agent and triethylamine, diisopropylethyl amine, N-methylmorpholine and the like can be used as a base. At this time, as asolvent, methylene chloride, diethyl ether, tetrahydrofuran, dioxane andthe like is used. Reductive amination followed by ester hydrolysis, aspreviously described in Scheme 7, furnishes the desired final product41, wherein A, R₁, R₂, R₃, R₄, X and Aa are as defined above (Scheme 8).A salt is optionally produced by the addition of an acid or base, suchas hydrogen chloride gas or hydrochloric acid. The correspondinghydroxamic acid or amide derivative 44, wherein A, R₁, R₂, R₃, R₄, R₆,R₁₈ (R₁₈ is either R₇ or OR₇) and X are as defined above, could besynthesized (Scheme 9) in an analogous manner starting with the acid 35by amide bond formation between acid 35 and amine (NHR₆R₇) orhydroxylamine (NHR₆OR₇), followed by ketal hydrolysis and reductiveamination, as previously described in Scheme 8. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid.

[0312] Homo analogues (here homo analogues means one carbon chainextended analogues) of compounds 37, 38, 41, 44 can be prepared by, forexample, the following synthetic scheme (Scheme 10).1,4-Dioxa-8-azaspiro[4.5]decane is reacted with 4′-fluoroacetonephenone45, as previously described in Scheme 1, to give acetonephenone 46. Themethyl ketone compound 46 is converted into arylalkanoate 47 using anoxidative rearrangement procedure. In this reaction thallium(III)nitrate, iodine-silver nitrate and the like is used as an oxidationagent and an alcoholic solvent (R₆OH) such as methanol or ethanol isused as a solvent. Ketal and ester hydrolysis followed by reductiveamination, as previously described in Scheme 1, generates the desiredhomo analog 49, wherein A, R₁, R₂, R₃, R₄, and X are as defined above. Asalt is optionally produced by the addition of an acid or base, such ashydrogen chloride gas or hydrochloric acid. Homo analogues of monopeptide 41 or compound 44 derived from the acid 48 can be prepared in ananalogous manner as previously described in Scheme 8 and Scheme 9.

[0313] Two carbon chain extended analogues of compounds 37, 38, 41, 44can be prepared by, for example, the following synthetic scheme (Scheme11). Compound 50 can be obtained by a Wittig or related reaction betweenaldehyde 2 and a Wittig reagent in the presence of a base. In thisreaction diethyl ethoxycarbonylmethanephosphonate,(ethoxycarbonylmethyl) triphenylphosphonium chloride,triphenyl(ethoxy-carbonylmethyl)phosphonium bromide and the like can beused as a Wittig reagent and lithium diisopropylamide, sodium hydride,potassium hydroxide and the like can be used as a base. Ketal hydrolysisunder acidic conditions followed by reductive amination, as previouslydescribed in Scheme 1, generates the desired olefinic analog 52, whereinA, R₁, R₂, R₃, R₄, R₆, and X are as defined above. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid. The corresponding olefinic acid analog 55,wherein A, R₁, R₂, R₃, R₄, and X are as defined above, can be obtainedby a basic hydrolysis process. In this case, lithium hydroxide, sodiumhydroxide and the like can be used as a base and aqueous methanol,ethanol, tetrahydrofuran and the like can be used as a solvent. Thecarbon-carbon double bond of compound 52 can be reduced by catalytichydrogenation in the presence of a metal catalyst such as palladium,platinum, rhodium and the like to give the reduced analog 53, wherein A,R₁, R₂, R₃, R₄, R₆ and X are as defined above. An alcohol such asmethanol, ethanol, isopropanol and the like, acetic acid,tetrahydrofuran, dioxane can be used as solvent in the hydrogenation.The corresponding propanic acid analog 54, wherein A, R₁, R₂, R₃, R₄ andX are as defined above, was produced by basic hydrolysis of 53, aspreviously described in Scheme 7. Alternatively, ester 50 is treatedwith a base to produce the acid 56, which in turn is treated with astrong acid to remove the protecting ketal group of 56, thus exposingthe terminal ketone for a reductive amination process (with hydrogen andcatalytic palladium) to generate the same compound 54. A salt isoptionally produced by the addition of an acid or base, such as hydrogenchloride gas or hydrochloric acid. Mono peptide 41 or compound 44analogues derived from compound 51 or 57 can be prepared in an analogousmanner as previously described in Scheme 8 and Scheme 9.

[0314] Malonic acid analogues of compounds 37, 38, 41, 44 can beprepared as described in Scheme 12 starting from compound 2. AKnoevenagel condensation between a malonic acid diester and the aldehyde2 yields compound 58. In this reaction sodium acetate, piperidine,piperidinium acetate, pyrrolidine, potassium acetate, sodium carbonateand the like can be used as a base, and an alcohol such as methanol,ethanol, isopropanol, methoxyethanol and the like can be used as asolvent. Ketal hydrolysis followed by reductive amination of piperidione59 with amine 6, as previously described in Scheme 1, gives the malonicacid analog 60, wherein A, R₁, R₂, R₃, R₄, R₆ (provided that in 60 R₆can not be hydrogen) and X are as defined above. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid. The diester group in compound 60 could beconverted to mono acid or diacid by a basic hydrolysis process, which iswell known in the art, to yield compound 61 wherein A, R₁, R₂, R₃, R₄,R₆ and X are as defined above. Mono peptide 41 or compound 44 analoguesderived from compound 59 can be prepared in an analogous manner aspreviously described in Scheme 8 and Scheme 9.

[0315] Ether analogues of compounds 37, 38, 41, 44 can be prepared by,for example, the following synthetic scheme (Scheme 13). The aldehydegroup in compound 2 is reduced by a reducing agent such as sodiumborohydride, in an alcoholic solvent, e.g., methanol to yield alcohol62. Alcohol 62 is alkylated with, for example, iodoacetate sodium saltto generate acid 63, which is then converted to ether analog 65, whereinA, R₁, R₂, R₃, R₄ and X are as defined above, using ketalhydrolysis/reductive amination sequence as previously described inScheme 1. A salt is optionally produced by the addition of an acid orbase, such as hydrogen chloride gas or hydrochloric acid. Mono peptide41 and compound 44 analogues derived from compound 64 can be prepared inan analogous manner as previously described in Scheme 8 and Scheme 9.

[0316] Sulfonamide or amide 72 can be conveniently prepared by a varietyof methods known in the art. According to one route (Scheme 14),1,4-dioxa-8-azaspiro[4.5]decane is reacted with 4-nitroarylfluoride 66in the presence of base such as pyridine or potassium carbonate toafford ketal 67. This reaction can be carried out in a polar solventsuch as anhydrous acetonitrile, acetone, dimethylformamide, or pyridine.The nitro group is then reduced by, for example, catalytic hydrogenationto provide aniline 68. The aniline 68 could be acylated with eithersulfonyl chlorides or acyl chlorides in the presence of base such astriethylamine or pyridine to give the corresponding acylation product69. Compound 69 could be optionally alkylated with appropriatealkylating agents (R₆-halo) in the presence of base such as potassiumcarbonate to give the alkylated product 70. Alternatively, a sequence ofreductive amination between aniline 68 and appropriate aldehydes orketones followed by acylation with R₉X₁Cl furnishes the same alkylatedproduct 70. Ketal hydrolysis followed by reductive amination ofpiperidiones 71 with amine 6 as previously described in Scheme 1, givesthe sulfonamide or amide analog 72, wherein A, X, X₁, R₁, R₂, R₃, R₄, R₆and R₉ are as defined above. A salt is optionally produced by theaddition of an acid or base, such as hydrogen chloride gas orhydrochloric acid.

[0317] Diacylated amine derivatives 78 are also readily prepared bymethods known in the literature. For example, as shown in Scheme 15, thehydrochloric salt of 4-piperidone is condensed with4-nitroarylfluorides, conveniently in pyridine, to give piperidone 74.The nitro group in 74 is then reduced to the corresponding aniline bycatalytic hydrogenation as previously described. Diacylation of aniline75 by R₉X₁Cl followed by R₁₀X₂Cl (R₉X₁Cl and R₁₀X₂Cl could be the samein some cases) gives the desired intermediate 77, which could beconverted to the final product 78, wherein A, X, X₁, X₂, R₁, R₂, R₃, R₄,R₆, R₉ and R₁₀ are as defined above, by a reductive amination process aspreviously described in Scheme 1.

[0318] Some of the compounds of the present invention are prepared by anovel solution phase methodology (Scheme 16). In this method the productis formed in solution phase reactions and excess reagents are removedfrom solutions by solid scavenging agents. Treatment of aniline 75 withexcess sulfonyl chloride and an resin base such as(piperidinomethyl)polystyrene in a solvent such as dichloromethane or1,4-dioxane for 1 to 24 hours at room temperature gives the desiredsulfonamide 76. The excess sulfonyl chloride is then removed by anucleophilic scavenging agent, for example, aminomethylated polystyreneresin. The intermediate piperidone 76 could be isolated by filtrationand evaporation. The imine formation between the piperidiones and excessarylethanolamines or aryloxypropanolamines is accomplished in a solventsuch as methanol and in a water scavenging agent such as trimethylorthoformate. The imine reduction is achieved by using a solid supportedborohydride such as Amberlite IRA-400 borohydride resin. The excessamine is readily removed by quenched with a carboxaldehyde resin such asformylpolystyrene. The final product 79, Wherein A, X, X₁, R₁, R₂, R₃,R₄, R₆ and R₉ are as defined above, could be purified by the same manneras described in Scheme 1.

[0319] The compounds of the present invention where acidic group R₅ isurea can be prepared starting from aniline 73, as shown in Scheme 17.Aniline 80 is available from 73 by treatment of 73 with strong acid suchas aqueous concentrated hydrochloric acid. Aniline 80 can be added toisocyanates to give the corresponding substituted urea 81. A reductiveamination between amine 6 and 81, as previously described, gives thedesired urea 82, wherein A, R₁, R₂, R₃, R₄, R₆, R₇ and X are as definedabove. A salt is optionally produced by the addition of an acid or base,such as hydrogen chloride gas or hydrochloric acid.

[0320] The compounds of the present invention where the cyclic amine isazetidine can be prepared as illustrated in Scheme 18. The alcohol of 83is protected, for example, as its t-butyldimethylsilyl(TBS) ether togive TBS derivative 84. The protecting diphenylmethyl group in 84 isthen removed by trearment of 84 with ammonium formate in the presence ofpalladium catalyst or raney nickle, typically in refluxing methanol.Condensation of azitidine 85 with arylfluoride 66 as before gives thekey intermediate 86. The alcohol of 86 is then converted to thecorresponding amine 88 by treatment with mesyl (Ms) chloride followed bybenzylamine. The epoxides 89, many of which are commercially availableor can be readily prepared as described in Scheme 19, are coupled withamine 88 by heating them neat or in a polar solvent. Preferably, thereaction is carried under refluxing methanol. The nitro group in 90 isthen reduced, for example, by sodium hydrosulfite, to give an aniline.The aniline is then acylated with sulfonyl chloride, acyl chloride orisocyanates followed by deprotection of benzyl group with ammoniumformate/palladium on carbon to give the desired azitidine 92, wherein A,R₁, R₂, R₃, R₄, R₉ and X₁ are as defined above. A salt is optionallyproduced by the addition of an acid or base, such as hydrogen chloridegas or hydrochloric acid.

[0321] Many of arylethanolamines or aryloxypropanolamines 6 arecommercially available or readily prepared by known methods [1. Guy, A.,Ferroud, D. C., Garreay, R., Godefroy-Falguieres A. Synthesis, 1992,821; 2. Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738; 3.Tominaga, M., Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa,K. Chem. Pharm. Bull. 1987, 35, 3699]. In one route (Scheme 19)equimolecular amounts of alcohol 93 and enantiomerically pure(2S)-glycidyl 3-nitrobenzene sulfonate 94 are dissolved in an organicsolvent such as acetone or N,N-dimethylformamide and treated with a basesuch as sodium hydride or potassium carbonate for 0.5 to 24 hours at atemperature of 20-100° C. to provide oxirane 89. The oxirane 89 isconverted to the corresponding amine 97 or 98, wherein A, R₁, R₂, and R₃are as defined above (provided that in 98 R₁, R₂, and R₃ can not bebenzyloxy), by regioselective ring opening of oxirane 89 with eitherlithium azide in a solvent such as hexamethylphosphoramide (HMPA)followed by reduction with, for example, triphenylphosphine in aqueoustetrahydrofuran, or with one equivalent of dibenzylamine followed byammonium formate/palladium on carbon reduction. The other enantiomer isavailable through an analogous preparative sequence with thecorresponding (2R)-glycidyl 3-nitrobenzene sulfonate.

[0322] One route to the desired arylethanolamines 6 is illustrated inScheme 20. Methylketones 99 are all available commercially or can beprepared by conventional methods disclosed in the art. Compound 99 canbe easily converted to the corresponding α-haloketone 100, wherein halois chlorine, bromine or iodine, using well known halogenation agentssuch as chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide andthe like. The resultant α-haloketone 100 is then reduced, for example,by sodium borohydride, to give the corresponding racemic alcohol 101. Anenantiomerically enriched alcohol 101 may be prepared by asymmetricreduction of α-haloketone 100 with chiral reducing agents such as (+) or(−)-B-chlorodiisopinocampheylborane (DIP-CI), R or S-Alpine borane,cis-(1R, 2S) or cis (1S, 2R)-oxazaborolidine and the like. The alcoholof intermediate 101 may be protected, for example, as its triethylsilylether. In some cases, however, the alcohol protecting group is notrequired. The halo compound 101 can be easily converted to thecorresponding benzylamine 102 by heating to 30-80° C. with large excessof benzylamine neat or as a solution in a polar solvent such astetrahydrofuran, acetonitrile or methanol for 1 to 24 hours. Theprotecting group is then removed, in the case of silyl ether, bytreatment of 102 with a fluoride agent such as tetrabutylammoniumfluoride (TBAF). Compound 103 is then subjected to catalytichydrogenation in the presence of ammonium formate/Pd to give the desiredaminoethanol 104, wherein A, R₁, R₂, and R₃ are as defined above. Thereduction is conveniently conducted in refluxing methanol in thepresence of a large excess of ammonium formate.

[0323] Alternatively, the halo compound 101 could be converted to thecorresponding amine 104 by either treatment with a sodium azide/sodiumiodide mixture in a polar solvent such as dimethyl sulfoxide,hexamethylphosphoramide and the like followed by catalytic hydrogenationin the presence of a metal catalyst such as palladium, platinum and thelike; or treatment with a base such as sodium hydroxide, potassiumcarbonate or the like followed by ammonia in a polar solvent such asmethanol, tetrahydrofuran or the like.

[0324] The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

[0325] The ability of compounds of this invention to treat or inhibitdisorders related to insulin resistance or hyperglycemia was confirmedwith representative compounds of this invention in the followingstandard pharmacological test procedures, which measured the bindingselectivity to the β₁, β₂, and β₃ adrenergic receptors. Binding to thereceptors was measured in Chinese Hamster ovary (CHO) cells that weretransfected with adrenergic receptors. The following briefly summarizesthe procedure used and results obtained.

[0326] Transfection of CHO cells with β₁ and β₂ adrenergic receptors:CHO cells were transfected with human β₁- or β₂-adrenergic receptors asdescribed in Tate, K. M., Eur. J. Biochem., 196:357-361 (1991).

[0327] Cloning of Human β₃-AR Genomic DNA: cDNA was constructed byligating four polymerase chain reaction (PCR) products using thefollowing primers: an ATG-Narl fragment, sense primer5′-CTTCCCTACCGCCCCACGCGCGATC3′ and anti-sense primer5′CTGGCGCCCAACGGCCAGTGGCCAGTC3′; a Narl-Accl fragment,5′TTGGCGCTGATGGCCACTGGCCGTTTG3′ as sense and5′GCGCGTAGACGAAGAGCATCACGAG3′ as anti-sense primer; an Accli-Stylfragment, sense primer 5′CTCGTGATGCTCTTCGTCTCACGCGC3′ and anti-senseprimer 5′GTGAAGGTGCCCATGATGAGACCCAAGG3′ and a Styl-TAG fragment, withsense primer 5′CCCTGTGCACCTTGGGTCTCATCATGG3′ and anti-sense primer5′CCTCTGCCCCGGTTACCTACCC3′. The corresponding primer sequences aredescribed in Mantzoros, C. S., et.al., Diabetes 45: 909-914 (1996). Thefour fragments are ligated into a pUC 18 plasmid (Gibco-BRL) andsequenced. Full length β₃ AR clones (402 amino acids) containing thelast 6 amino acids of hβ₃-AR are prepared with the β₃-βARpcDNA3 fromATTC.

[0328] Binding Procedure: Clones expressing receptor levels of 70 to 110fmoles/mg protein were used in the test procedures. CHO cells were grownin 24-well tissue culture plates in Dulbecco's Modified Eagle Media with10% fetal bovine serum, MEM non-essential amino acids,Penicillin-Streptompycin and Geneticin. On the day of test procedure,growth medium was replaced with preincubation media (Dulbecco's ModifiedEagle, Media) and incubated for 30 minutes at 37° C. Preincubationmedium was replaced with 0.2 ml treatment medium containing DMEM mediacontaining 250 μM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbicacid with test compound dissolved in DMSO. Test compounds were testedover a concentration range of 10⁻⁹ M to 10⁻⁵ M for β₃ cells and 10⁻⁸ to10⁻⁴ M for β₁ and β₂ transfected cells. Isoproterenol (10⁻⁵ M) was usedas an internal standard for comparison of activity. Cells were incubatedat 37° C. on a rocker for 30 min with the β₃ cells and 15 min for β₁ andβ₂ cells. Incubation was stopped with the addition of 0.2N HCl andneutralized with 2.5N NaOH. The plates, containing the cells andneutralized media, were stored at −20 degrees celsius until ready totest for cAMP using the SPA test kit (Amersham).

[0329] Data Analysis and Results: Data collected from the SPA testprocedure were analyzed as percent of the maximal isoproterenol responseat 10⁻⁵ M. Activity curves were plotted using the SAS statistical andgraphics software. EC₅₀ values were generated for each compound and themaximal response (IA) developed for each compound is compared to themaximal response of isoproternol at 10⁻⁵ M from the following formula:

IA=% activity compound/% activity isoproterenol

[0330] Table I shows the β₃-adronergic receptor EC₅₀ and IA values forthe representative compounds of this invention that were evaluated inthis standard pharmacological test procedure. These results show thatcompounds of the present invention have activity at the β₃-adrenergicreceptor. The compounds of this invention had weaker or no activity atβ₁ and/or β₂-adrenergic receptor. TABLE I Compound No. EC₅₀(β₃, μM)IA(β₃) Example 63 20 1 Example 64 3 1 Example 65 34 1.1 Example 66 80.81 Example 67 9 1.06 Example 68 8 1 Example 69 6 1 Example 70 0.7 1.2Example 71 1 1.2 Example 72 89 0.68 Example 73 40 0.71 Example 74 2330.23 Example 75 2 1.08 Example 76 33 0.94 Example 77 6 1.03 Example 78 91.1 Example 79 167 0.56 Example 80 1 1.1 Example 81 12 0.89 Example 8263 1.07 Example 83 33 0.68 Example 84 10 1.19 Example 85 34 0.94 Example86 380 0.69 Example 87 230 1 Example 88 9 1 Example 89 24 1.1 Example 9086 1.2 Example 91 13 1.2 Example 92 3 1.1 Example 93 0.4 1 Example 95660 0.59 Example 96 6 0.93 Example 97 49 0.9 Example 98 5 1 Example 99132 0.97 Example 100 43 0.9 Example 122 179 0.46 Example 125 760 0.36Example 131 1,320 0.52 Example 136 900 0.9 Example 146 17 0.91 Example179 89 0.85 Example 180 4 1 Example 181 0.56 Example 182 197 0.86Example 183 42 0.84 Example 184 65 1.1 Example 185 53 0.69 Example 186179 1.1 Example 187 37 1.03 Example 188 9 0.91 Example 189 10 1.3Example 190 23 1.12 Example 191 4 1 Example 192 20 0.97 Example 193 50.9 Example 194 7,124 0.88 Example 195 195 0.98 Example 196 9 1.1Example 197 40 0.94 Example 198 1 0.97 Example 199 8 1 Example 200 4 1.1Example 201 55 1.1 Example 202 8 1.2 Example 203 16 1.1 Example 204 31.2 Example 205 7 1.2 Example 206 16 0.94 Example 207 9 1 Example 208 130.97 Example 209 2 1 Example 210 55 1.36 Example 211 8 1 Example 212 91.1 Example 213 6 0.97 Example 255 1,360 0.72 Example 256 910 0.85Example 257 610 0.88 Example 258 3,126 0.7 Example 259 916 0.97 Example260 3,755 0.63 Example 261 12,185 0.73 Example 263 8 0.93 Example 2641,830 0.37 Example 265 94 0.8 Example 266 10 0.86 Example 267 15,4000.99 Example 268 797 0.64 Example 270 21 1.09 Example 271 20 0.84Example 272 1,553 0.57 Example 273 3,840 1.05 Example 274 165 1.15Example 275 100 0.73 Example 276 1 1.1 Example 277 3 0.58 Example 278 101.04 Example 279 470 0.74 Example 280 20 1.16 Example 281 9 1.14 Example282 22 0.63 Example 283 10 0.81 Example 284 20 0.87 Example 285 39 0.76Example 286 9 0.91 Example 287 10 0.92 Example 288 66 1.24 Example 28970 0.59 Example 290 34 0.72 Example 291 13 1.07 Example 292 3 0.75Example 293 210 0.94 Example 294 33 1.07 Example 295 6 0.87 Example 2968 0.81 Example 297 16 1 Example 298 59 0.78 Example 299 0.6 1.1 Example300 55 0.78 Example 301 30 0.95 Example 302 10 0.95 Example 303 20 0.96Example 304 110 0.35 Example 305 1 1 Example 306 5 1.1 Example 307 4 1Example 308 2 1.4 Example 309 1 1 Example 310 25 1 Example 311 210 0.82Example 312 1 1.1 Example 313 13 1 Example 315 1 1.2 Example 317 50 0.97Example 318 13 1 Example 319 4,160 0.79 Example 320 11 0.87 Example 32113 1.05 Example 322 2 0.89 Example 323 35 0.92 Example 324 4 0.9 Example325 4 1 Example 326 79 1.3 Example 327 6 0.86 Example 328 8 0.89 Example329 15 0.9 Example 330 12 0.98 Example 331 9 1 Example 332 20 1.1Example 333 13 0.83 Example 334 40 0.91 Example 335 3 0.98 Example 33620 0.82 Example 337 29 0.72 Example 338 4 1 Example 339 10 0.89 Example342 3 1 Example 343 20 0.86 Example 345 4 1 Example 346 1,580 0.76Example 347 14 0.91 Example 348 95 0.63 Example 349 390 1.26 Example 3501,070 1.26 Example 351 888 0.76 Example 352 109 1.02 Example 353 1,3800.97 Example 354 283 0.73 Example 357 96 0.87 Example 358 33 1.1 Example359 73 0.91 Example 360 155 0.54 Example 361 1,134 0.55 Example 362 300.9 Example 371 10 0.91 Example 372 127 1 Example 373 9 1.1 Example 3749 1.2 Example 375 1 1 Example 376 1 1 Example 377 16 0.66 Example 378 560.94 Example 379 13 0.93 Example 380 8 1.1 Example 381 57 0.97 Example382 19 0.64 Example 383 740 0.64 Example 384 199 0.64 Example 385 551.12 Example 386 51 0.89 Example 387 168 0.56 Example 388 740 0.75Example 389 50 0.61 Example 390 14 0.82 Example 391 337 0.81 Example 39218 0.9 Example 393 10 1 Example 394 66 1.3 Example 411 954 0.49 Example412 1,329 0.56 Example 413 580 0.73 Example 415 537 0.35 Example 416 530.48 Example 417 24 0.71

[0331] Evaluation in β₃ Knockout(KO) and β₃ Transgenic(Tg) Mice: Theability of compounds of this invention to treat or inhibit disordersrelated to insulin resistance or hyperglycemia was also confirmed withrepresentative compounds of this invention in an in vivo standardpharmacological test procedure which compared thermogenesis intransgenic mice (Tg mice) and β₃-knockout mice (KO mice). The procedureused and results obtained are provided below.

[0332] β₃-Adrenergic receptor knockout mice and β₃ human transgenic miceare created on an inbred FVB background (Susulic, V.S., et.al., J. Biol.Chem., 1995, 270 (49), 29483-29492). Female FVB β₃ transgenic and β₃knockout mice were used to determine in vivo activity and selectivity ofβ₃ agonists. Compounds selected for in vivo testing had β₃ EC₅₀<30 nmand were full agonists in CHO cells expressing human β₃ receptors. Thesecompounds were also selective in being 100-fold less responsive andpartial agonists when tested in β₁ and β₂ transfected CHO cells.Compounds were tested for increased thermogenesis using the Oxymaxindirect calorimeter (Columbus Instruments, Columbus, Ohio). Fed animalswere placed in chambers for 3 hours to obtain baseline O₂ and CO₂values. Eight fed mice were weighed in pairs and placed in 4 chambers,two per chamber. The relative gas content of each chamber was sampledand recorded at 10 to 12 minute intervals. For each sample, energyexpenditure values were calculated by the Oxymax and expressed askcal/hr. After 3 hours of baseline measurement, the mice were removed,treated and replaced in the chambers. The β₃ agonists were injected atdoses between 0.1 and 20 mg/kg i.p. and between 1.0 and 30 mg/kg fororal administration. Compounds in 10 mM or 10 mg/ml DMSO solutions weresuspended in 0.5% methylcellulose: 0.1% tween-80 and injected i.p. oradministered by oral gavage. Some compounds were suspended in 5.0%tween-80 for oral administration. Post-treatment kcal/hr values weretaken between 40 minutes and 2.5 hours later. The 6 to 10 samplesections of the pre-treatment and post-treatment periods, which appearto best represent stable resting thermogenesis, were selected. Each ofthese sample values was corrected for body weight and used such thateach pair of mice serves as its own baseline for both T test and percentincrease in thermogenesis calculations. An ANOVA and a one sided T test(H1: Post>Pre) are performed using the SAS software modified to downweight extreme values. In a separate set of calculations, values thatappear to be too high to represent resting thermogenesis are discarded(activity monitor sampling associated spikes in thermogenesis withambulatory activity). The mean baseline value for each chamber issubtracted from mean post-treatment value for that chamber. Thisbaseline-subtracted value is divided by the mean baseline value andmultiplied by 100 to obtain a percent increase in thermogenesis for eachchamber. The combined mean percent increase, standard deviation, andstandard error of the mean for each chamber is calculated. Compoundswere considered active if they were able to produce a statisticallysignificant 15% increase in thermogenesis in β₃ transgenic mice and nosignificant increase in β₃ knockout mice. The results are shown in thetable below. Thermogenesis in β3 Knockout(KO) and β3 Transgenic(Tg) MiceThermogenesis Thermogenesis Compound No# (Tg mice) (KO mice) Example 6330 ± 8% 16 ± 4% Example 84 30 ± 4% −2 ± 4% Example 180 42 ± 4%  9 ± 5%Example 186  77 ± 12% 16 ± 7% Example 189 33 ± 7%  6 ± 3%

[0333] Based on the results obtained in these standard pharmacologicaltest procedures, representative compounds of this invention have beenshown to be selective β₃ adrenergic receptor agonists and are thereforeuseful in treating metabolic disorders related to insulin resistance orhyperglycemia (typically associated with obesity or glucoseintolerance), atherosclerosis, gastrointestinal disorders, neurogeneticinflammation, glaucoma, ocular hypertension, and frequent urination; andare particularly useful in the treatment or inhibition of type IIdiabetes, and in modulating glucose levels in disorders such as type Idiabetes. As used herein, the term modulating means maintaining glucoselevels within clinically normal ranges.

[0334] As used in accordance with this invention, the term providing aneffective amount means either directly administering such a compound ofthis invention, or administering a prodrug, derivative, or analog whichwill form an effective amount of the compound of this invention withinthe body.

[0335] It is understood that the effective dosage of the activecompounds of this invention may vary depending upon the particularcompound utilized, the mode of administration, the condition, andseverity thereof, of the condition being treated, as well as the variousphysical factors related to the individual being treated. As used inaccordance with invention, satisfactory results may be obtained when thecompounds of this invention are administered to the individual in needat a daily dosage of from about 0.1 mg to about 1 mg per kilogram ofbody weight, preferably administered in divided doses two to six timesper day, or in a sustained release form. For most large mammals, thetotal daily dosage is from about 3.5 mg to about 140 mg. It is preferredthat the administration of one or more of the compounds herein begin ata low dose and be increased until the desired effects are achieved.

[0336] Such doses may be administered in any manner useful in directingthe active compounds herein to the recipient's bloodstream, includingorally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, intranasally,vaginally, and transdermally. For the purposes of this disclosure,transdermal administrations are understood to include alladministrations across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0337] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).

[0338] In some cases it may be desirable to administer the compoundsdirectly to the airways in the form of an aerosol.

[0339] The compounds of this invention may also be administeredparenterally or intraperitoneally. Solutions or suspensions of theseactive compounds as a free base or pharmacologically acceptable salt canbe prepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared, in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparation contain a preservativeto prevent the growth of microorganisms.

[0340] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene, glycol), suitable mixtures thereof, and vegetable oils.

[0341] Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin.

[0342] Water soluble suppository bases, such as polyethylene glycols ofvarious molecular weights, may also be used.

[0343] The compounds of the present invention also possess utility forincreasing lean meat deposition and/or improving lean meat to fat ratioin edible animals, i.e. ungulate animals and poultry.

[0344] Animal feed compositions effective for increasing lean meatdeposition and for improving lean meat to fat ratio in poultry, swine,sheep, goats, and cattle are generally prepared by mixing the compoundsof the present invention with a sufficient amount of animal feed toprovide from about 1 to 1000 ppm of the compound in the feed. Animalfeed supplements can be prepared by admixing about 75% to 95% by weightof a compound of the present invention with about 5% to about 25% byweight of a suitable carrier or diluent. Carriers suitable for use tomake up the feed supplement compositions include the following: alfalfameal, soybean meal, cottonseed oil meal, linseed oil meal, sodiumchloride, cornmeal, cane molasses, urea, bone meal, corncob meal and thelike. The carrier promotes a uniform distribution of the activeingredients in the finished feed into which the supplement is blended.It thus performs an important function by ensuring proper distributionof the active ingredient throughout the feed. The supplement is used asa top dressing for the feed, it likewise helps to ensure uniformity ofdistribution of the active material across the top of the dressed feed.

[0345] The preferred medicated swine, cattle, sheep and goat feedgenerally contain from 0.01 to 400 grams of active ingredient per ton offeed, the optimum amount for these animals usually being about 50 to 300grams per ton of feed. The preferred poultry and domestic pet feedusually contain about 0.01 to 400 grams and preferably 10 to 400 gramsof active ingredient per ton of feed.

[0346] For parenteral administration the compounds of the presentinvention may be prepared in the form of a paste or a pellet andadministered as an implant, usually under the skin of the head or ear ofthe animal in which increase in lean meat deposition and improvement inlean mean to fat ratio is sought. In general, parenteral administrationinvolves injection of a sufficient amount of the compounds of thepresent invention to provide the animal with 0.001 to 100 mg/kg/day ofbody weight of the active ingredient. The preferred dosage for swine,cattle, sheep and goats is in the range of from 0.001 to 50 mg/kg/day ofbody weight of active ingredient, whereas, the preferred dose level forpoultry and domestic pets is usually in the range of from 0.001 to 35mg/kg/day of body weight.

[0347] Paste formulations can be prepared by dispersing the activecompounds in a pharmaceutically acceptable oil such as peanut oil,sesame oil, corn oil or the like. Pellets containing an effective amountof the compounds of the present invention can be prepared by admixingthe compounds of the present invention with a diluent such as carbowax,carnuba wax, and the like, and a lubricant, such as magnesium or calciumstearate, can be added to improve the pelleting process. It is, ofcourse, recognized that more than one pellet may be administered to ananimal to achieve the desired dose level which will provide the increasein lean meat deposition and improvement in lean meat to fat ratiodesired. Moreover, it has been found that implants may also be madeperiodically during the animal treatment period in order to maintain theproper drug level in the animal's body. For the poultry and swineraisers, using the method of the present invention yields leaneranimals.

[0348] Additionally, the compounds of this invention are useful inincreasing the lean mass to fat ratio in domestic pets, for the petowner or veterinarian who wishes to increase leanness and trim unwantedfat from pet animals, the present invention provides the means by whichthis can be accomplished.

[0349] The following procedures describe the preparation ofrepresentative compounds of this invention.

EXAMPLE 1 (1R)-2-Amino-1-(3-chloro-phenyl)-ethanol hydrochloride

[0350] Lithium azide (7.5 g, 150 mmol) was added to a solution of(1R)-1-(3-chloro-phenyl)oxirane (15.5 g, 100 mmol inhexamethylphososphoramide(HMPA) (70 ml). After being stirred at roomtemperature for 16 hours the suspension was poured into ice-water andthe mixture was extracted with diethyl ether. The combined extracts weredried over magnesium sulfate (MgSO₄) and concentrated. The residue wasdissolved in 550 mL of tetrahydrofuran(THF)/water(H₂O) (10:1) andtriphenylphosphine(30 g, 114 mmol) was added. After overnight stirringat room temperature, the solvents were removed and the residue waspurified by column chromatography on silica gel usingtriethylamine-methanol-methylene chloride(CH₂Cl₂) (1:1:8) as the eluentto give the title compound as a free base.

[0351] The title compound was characterized as its hydrochloric salt:The free base from above was then dissolved in diethyl ether and slowlytreated with hydrogen chloride gas. The precipitate was collected byfiltration to yield 15 g (72%) of the title compound as a white powder;¹H NMR (300 MHz, DMSO-d₆) δ2.83 (dd, J=12.8, 9.5 Hz, 1 H), 3.06 (dd,J=12.8, 3.2 Hz, 1 H), 4.80-4.90 (m, 1 H), 6.22 (d, J=4.0 Hz, 1 H),7.10-7.75 (m, 4 H), 8.08 (brs, 2 H); MS (ES) m/z: 171.7, 173.7 (MH⁺);HRMS Calcd. for C₈H₁₀ClNO(MH⁺): 172.0529. Found: 172.0531.

EXAMPLE 2 (2S)-2-Phenoxymethyl-oxirane

[0352] A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl3-nitrobenzenesulfonate (25.9 g, 100 mmol) in 500 mL of acetone wastreated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) andstirred at reflux for 1 day. The suspension was cooled to ambienttemperature; the solid was filtered; and the filtrate was concentratedto dryness. The residue was partitioned between methylene chloride andwater. The aqueous layer was extracted with CH₂Cl₂. The organic layerswere combined and dried over MgSO₄ and concentrated to give the titlecompound (15.0 g, 99%) as an orange oil; ¹H NMR (300 MHz, CDCl₃) δ2.76(dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30-3.40 (m, 1H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H),6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH⁺).

EXAMPLE 3 (2S)-1-Amino-3-phenoxypropan-2-ol

[0353] The title compound was prepared from (2S)-2-phenoxymethyl-oxirane(which was obtained in Example 2) according to the procedure of Example1 with one change. The free base was obtained as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ2.56 (dd, J=12.8, 6.3 Hz, 1 H), 2.67 (dd, J=12.8,4.9 Hz, 1 H), 3.65-3.75 (m, 1 H), 3.82 (dd, J=9.8, 6.0 Hz, 1 H), 3.93(dd, J=9.8, 5.0 Hz, 1 H), 6.85-6.95 (m, 3 H), 7.20-7.30 (m, 2 H); MS(ES) m/z: 167.7 (MH⁺); HRMS Calcd. for C₉H₁₃NO₂(M⁺): 167.0946. Found:167.0945.

EXAMPLE 4 (2S)-1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol

[0354] The title compound was prepared from(2S)-2-(4-benzyloxy-phenoxymethyl-oxirane (EP 0 714 883) according tothe procedure of Example 1 with one change. The free base was obtainedas as a white solid; ¹H NMR (300 MHz, CDCl₃) δ2.50-2.70 (m, 2 H), 3.33(brs, 2 H), 3.60-3.90 (m, 3 H), 5.02 (s, 2 H), 6.90 (d, J=6.7 Hz, 2 H),6.93 (d, J=6.7 Hz, 2 H), 7.25-7.50 (m, 5 H); MS (ES) m/z: 274.1 (MH⁺);HRMS Calcd. for C₁₆H₁₉NO₃(M⁺): 273.1365. Found: 273.1347. Anal. Calcd.for C₁₆H₁₉NO₃: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.39; H, 6.80; N,5.23.

EXAMPLE 5 (2S)-1-Amino-3-(4-hydroxy-phenoxy)-propan-2-ol

[0355] A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol(0.9 g, 3.3 mmol) (which was obtained in Example 4), 0.2 mL of aceticacid and 10% palladium on carbon (Pd/C) (0.3 g) in 70 mL of ethanol waspressurized with 20 psi hydrogen and shaken over 2 hours. The catalystwas then removed by filtering through a short pad of silica gel and thesolvent was removed to give the title compound as an off-white solid; ¹HNMR (300 MHz, DMSO-d₆) δ1.86 (s, 1 H), 2.66 (dd, J=12.8, 5.3 Hz, 1 H),2.85 (dd, J=12.8, 3.5 Hz, 1 H), 3.79-3.95 (m, 3 H), 6.67 (d, J=6.6 Hz, 2H), 6.75 (d, J=6.6 Hz, 2H); MS (ES) m/z: 183.1 (MH⁺); HRMS Calcd. forC₉H₁₃NO₃(MH⁺): 183.0895. Found: 183.0892.

EXAMPLE 6N-[2-Benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide

[0356]N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide (EP 0659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL ofN,N-dimethylformamide(DMF) and treated with dibenzylamine (22.0 g, 110mmol). The mixture was stirred at room temperature overnight and thenthe solvent was removed. The residue was purified by silica gelchromatography using 20-50% ethyl acetate/hexanes as eluent to give thetitle compound as a white solid; ¹H NMR (300 MHz, CDCl₃) δ2.94 (s, 3 H),3.77 (s, 2 H), 3.82 (s, 2 H), 5.16 (s, 2 H), 6.75 (brs, 1 H), 6.96 (d,J=8.7 Hz, 1 H), 7.20-7.50 (m, 15 H), 7.67 (dd, J=8.7, 2.1 Hz, 1 H), 8.10(d, J=2.1 Hz, 1 H); MS (ES) m/z: 515.2 (MH⁺); HRMS Calcd. forC₃₀H₃₀N₂O₄S(M⁺): 514.1926. Found: 514.1927.

EXAMPLE 7N-[2-Benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide

[0357] Sodium borohydride (0.37 g, 9.7 mmol) was added in portions to astirred solution ofN-[2-benzyloxy-5-(2-dibenzylamino-1oxo-ethyl)-phenyl]-methanesulfonamide(1.0 g, 1.9 mmol) (which was obtained in Example 6) in 20 mL ofmethanol/THF (5:2) at room temperature and the resulting solution wasstirred for 2 hours. Methylene chloride was added and the resultingsolution was washed with aqueous sodium bicarbonate, dried over MgSO₄and the solvents were removed. Recrystallization from methylenechloride/hexanes gave the title compound as a crystalline solid; ¹H NMR(300 MHz, CDCl₃) δ2.58 (d, J=6.7 Hz, 2 H), 2.86 (s, 2 H), 2.92 (s, 2 H),3.55 (d, J=13.5 Hz, 2 H), 3.70 (d, J=13.5 Hz, 2 H), 4.11 (s, 1 H), 4.64(t, J=6.7 Hz, 1 H), 5.10 (s, 2 H), 6.92 (d, J=8.5 Hz, 1 H), 7.00 (dd,J=8.5, 2.0 Hz, 1 H), 7.20-7.50 (m, 16 H), 7.89 (brs, 1 H); MS (ES) m/z:517.1 (MH⁺); HRMS Calcd. for C₃₀H₃₂N₂O₄S(M⁺): 516.2083. Found: 516.2074.

EXAMPLE 8N-[2-Benzyloxy-5-(2-amino-(1R)-1-hydroxy-ethyl)-phenyl]-methanesulfonamide

[0358] A mixture ofN-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide(EP 0 659 737) (4.48 g, 8 mmol) and sodium azide (0.65 g, 10 mmol) in100 mL of HMPA was stirred at 60° C. overnight. After cooling to roomtemperature the mixture was diluted with diethyl ether, washed withwater, dried over sodium sulfate(Na₂SO₄) and concentrated under reducedpressure. The residue was dissolved in 200 mL of THF/H₂O (10:1) andtriphenylphosphine (2.62 g, 10 mmol) was added. After overnight stirringat room temperature, the solvents were removed and the residue waspartitioned between ethyl acetate and water. The organic layers werecombined, and dried over MgSO₄ and concentrated. The residue wasredissolved in 100 mL of THF and tetrabutylammonium fluoride(TBAF) (10mL, 1 M solution in THF) was added. The reaction was stirred for 2 hoursthen the solvent was removed in vacuo. The residue was purified bycolumn chromatography on silica gel using triethylamine-methanol-CH₂Cl₂(1:1:3) to give the title compound as white solid; MS (ES) m/z: 337.4(MH⁺).

EXAMPLE 9N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl[-methanesulfonamide

[0359] To a stirred suspension ofN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl[-methanesulfonamide(1.03 g, 2 mmol) which was obtained in Example 7) and 10% palladium oncarbon (Pd/C)(0.4 g) in methanol (100 mL) at room temperature was addedanhydrous ammonium formate (HCO₂NH₄)(1.26 g, 20 mmol) under a nitrogenatmosphere. The resulting mixture was refluxed for 2 hours. Aftercooling to room temperature the catalyst was removed by filtrationthrough a celite pad and washed with methanol. The filtrate isevaporated under reduced pressure to give the titled compound (Leclerc,G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowishsolid; ¹H NMR (300 MHz, DMSO-d₆) δ2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75(dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H),6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1Hz, 1 H), 8.44 (s, 1H); MS (ES) m/z: 246.7 (MH⁺); HRMS Calcd. forC₉H₁₄N₂O₄S(M⁺): 246.0674. Found: 246.0672.

EXAMPLE 10N-[5-(2-Amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0360] Method A: A mixture ofN-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide(EP 0 659 737) (8.60 g, 15.3 mmol) and benzylamine (21.4 g, 200 mmol)was heated at 60° C. for 24 hours. The reaction mixture was cooled,diluted with hexanes (500 mL), and the residue was washed with diethylether. The combined solvents were removed and the residue was purifiedby silica gel column eluting with 30 to 100% diethyl ether/hexanes. Thefractions with molecular weight of 540 were concentrated andre-dissolved in 200 mL of THF and TBAF (20 mL, 1.0 M solution in THF)was added. After stirring at room temperature for 4 hours the reactionmixture was then poured into water and extracted with CH₂Cl₂. Theorganic layers were passed through a short pad of silica gel elutingwith 10% methanol/CH₂Cl₂. The solvents were removed and the residue wasdissolved in methanol (200 mL). 10% Pd/C (0.6 g) and anhydrous HCO₂NH₄(6.3 g, 100 mmol) were added. The resulting mixture was refluxed under anitrogen atmosphere for 2 hours. After cooling to room temperature thecatalyst was removed by filtration through a celite pad and washed withmethanol. The filtrate was evaporated under reduced pressure to give thetitle compound as an off-white solid; ¹H NMR (300 MHz, MeOH-d₄) δ2.95(s, 3 H), 2.99 (dd, J=9.7, 9.2 Hz, 1 H), 3.07 (dd, J=9.7, 3.6 Hz, 1 H),4.75 (dd, J=9.2, 3.6 Hz, 1 H), 6.90 (d, J=8.3 Hz, 1 H), 7.12 (dd, J=8.3,2.1 Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7(MH⁺); HRMS Calcd. for C₉H₁₄N₂O₄S: 246.0674. Found: 246.0672.

[0361] Method B: To a stirred solution ofN-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(EP 0 659 737) (15.05 g, 0.376 mol) in dimethyl sulfoxide (300 MHz,DMSO-d₆) (150 mL) was added sodium iodide (3.76 g, 0.376 mol) and sodiumazide (9.48 g, 0.150 mol). The mixture was stirred for 5 days undernitrogen atmosphere. The reaction mixture was poured onto water andextracted three times with ethyl acetate. The combined organic layerswere dried over sodium sulfate and concentrated. The residue wastriturated with water and hexanes. Recovered yellow solid as ofN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide(12.85 g, 94%); ¹NMR (300 MHz, CDCl₃) δ2.93(s, 3 H), 3.45(d, J=9.0 Hz, 2H), 3.46(m, 1 H), 5.11(s, 2 H), 6.80(s,1 H), 6.99(d, J=8.4 Hz, 1 H),7.15(dd, J=6 Hz, 2.1 Hz, 1H), 7.26(s, 1 H), 7.39(s, 5 H), 7.53(d, J=2.1Hz, 1 H); MS (ES) m/z: 361.4 ((M−H)⁻, 70%). A mixture ofN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide(12.85 g, 0.037 mol) and 10% Pd/C (2.75 g) in ethanol (100 mL) washydrogenated under 45 psi for two days. The reaction mixture wasfiltered through celite and concentrated. The title compound wasrecovered as a tan solid. The product was found to be identical withthat prepared by method A.

EXAMPLE 118-Benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one

[0362] The title compound was prepared from8-benzyloxy-5-hydroxy-3,4-dihydro-1H-quinolin-2-one (Tominaga, M.,Ogawa, H., Yo, E. Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem. Pharm.Bull. 1987, 35, 3699) according to the procedure of Example 2; ¹H NMR(300 MHz, DMSO-d₆) δ2.41 (t, J=7.1 Hz, 2 H), 2.69 (dd, J=5.1, 2.7 Hz, 1H), 2.75-2.86 (m, 4 H), 3.78 (dd, J=11.4, 6.3 Hz, 1 H), 4.23 (dd,J=11.4, 2.6 Hz, 1 H), 5.09 (s, 2 H), 6.54 (d, J=9.0 Hz, 2 H), 6.86 (d,J=9.0 Hz, 2 H), 7.25-7.45 (m, 3 H), 7.51 (d, J=8.2 Hz, 2 H), 9.08 (s, 1H); MS (ES) m/z: 326.0 (MH⁺); HRMS Calcd. for C₁₉H₂₀NO₄(MH⁺): 326.1392.Found: 326.1343. Anal. Calcd. for C₁₉H₁₉NO₄: C, 70.14; H, 5.89; N, 4.30.Found: C, 70.14; H, 5.69; N, 4.20.

EXAMPLE 125-(3-Amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one

[0363] Dibenzylamine (1.46 g, 7.4 mmol) was added to a stirred solutionof 8-benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Example 11) (2.0 g, 6.2 mmol) in 100 mL ofmethanol. After refluxing overnight the mixture was cooled down to roomtemperature and 10% Pd/C (0.5 g) and HCO₂NH₄ (3.15 g, 50 mmol) wereadded. The suspension was refluxed for another hour. After cooling thesuspension the reaction mixture was filtered through celite. Thefiltrate was concentrated to give the title compound as a pale greysolid; ¹H NMR (300 MHz, DMSO-d₆) δ2.42(t, J=7.1 Hz, 2 H), 2.74 (dd,J=12.8, 8.2 Hz, 1 H), 2.81 (t, J=7.0 Hz, 2 H), 2.95 (dd, J=12.8, 3.4 Hz,1 H), 3.65-3.95 (m, 3 H), 6.45 (d, J=8.8 Hz, 2 H), 6.62 (d, J=8.8 Hz, 2H), 8.38 (s, 1 H), 8.77 (brs, 1 H); MS (ES) m/z: 252.9 (MH⁺)); HRMSCalcd. for C₁₂H₁₆N₂O₄(M⁺): 252.1188. Found: 252.1199.

EXAMPLE 13N-Benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide

[0364] The title compound was prepared fromN-benzyl-N-(2-benzoxy-5-hydroxy-phenyl)-methanesulfonamide (Kaiser, C.;Jen, T.; Garvey, E.; and Bowen, W. D. J. Med. Chem. 1977, 20, 687)according to the procedure of Example 2 as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ2.63(dd, J=5.1, 2.6 Hz, 1 H), 2.80(t, J=4.9 Hz, 1 H),3.10-3.20(m, 1 H), 3.66(dd, J=11.4, 6.6 Hz, 1 H), 4.16(dd, J=11.4, 2.6Hz, 1 H), 4.73(brs, 2 H), 5.12(s, 2 H), 6.69 (d, J=3.1 Hz, 1 H),6.88(dd, J=9.1, 3.1 Hz, 1 H), 7.08 (d, J=9.1 Hz, 1 H), 7.15-7.60(m, 10H); MS (ES) m/z: 439.9 (MH⁺, 100%); HRMS Calcd. for C₂₄H₂₅NO₅S (M⁺):439.1454. Found: 439.1457.

EXAMPLE 14N-[5-((2S)-3-Amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide

[0365] The title compound was prepared fromN-benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide(which was obtained in Example 13) according to the procedure of Example12 as a pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.61(dd, J=12.7, 6.1Hz, 1 H), 2.75(dd, J=12.7, 3.5 Hz, 1 H), 2.86(s, 3 H), 3.69-3.90(m, 3H), 6.55(dd, J=8.7, 3.1 Hz, 1 H), 6.70(d, J=8.7 Hz, 1 H), 6.75 (d, J=3.1Hz, 1 H); MS (ES) m/z: 276.8 (MH⁺, 100%); HRMS Calcd. for C₁₀H₁₆N₂O₅S(M⁺): 276.0780. Found: 276.0792.

EXAMPLE 15 Benzoic acid 4-benzyloxy-3-nitro-phenyl ester

[0366] A mixture of benzoic acid 4-hydroxy-3-nitro-phenyl ester (Tapia,R.; Torres, G. and Valderrama, J. A. Synth. Commun. 1986, 16, 681)(20.7g, 80 mmol), benzyl bromide (42.75 g, 250 mmol), potassium carbonate(48.3 g, 350 mmol) and DMF(300 mL) was stirred at room temperature for 2days. After removing the solvent the residue was dissolved in water andextracted with CH₂Cl₂. The organic extracts were dried (MgSO₄) andconcentrated. The product was purified by flash silica gelchromatography eluting with CH₂Cl₂ to give the title compound as a paleyellowish solid (25.1 g, 90%); ¹H NMR (300 MHz, CDCl₃) δ5.27(s, 2 H),7.17(d, J=9.1 Hz, 1 H), 7.30-7.55(m, 8 H), 7.60-7.70(m, 1 H), 7.80(d,J=2.9 Hz, 1 H), 8.15-8.25(m, 2 H); MS (ES) m/z: 345.0 (MH⁺, 100%); HRMSCalcd. for C₂₀H₁₅NO₅(M⁺): 349.0951. Found: 349.0952.

EXAMPLE 16 Benzoic acid 3-amino-4-benzyloxy-phenyl ester

[0367] A Parr hydrogenator was charged with platinum(IV) oxide(PtO₂)(0.3g) and a solution of benzoic acid 4-benzyloxy-3-nitro-phenyl ester(5.23g, 15 mmol) (which was obtained in Example 15) in methanol (80 mL) andCH₂Cl₂(40 mL). This mixture was then hydrogenated at 5 psi of hydrogenat 0˜10° C. for 2 hours. The reaction mixture was filtered through ashort pad of celite and concentrated. Recrystallization fromCH₂Cl₂/hexanes gave the title compound as a white solid (3.80 g, 79%);¹H NMR (300 MHz, CDCl₃) δ5.09(s, 2 H), 6.57(dd, J=10.1, 2.7 Hz, 1 H),7.10(d, J=2.7 Hz, 1 H), 7.30-7.50(m, 8 H), 7.55-7.65(m, 1 H),8.15-8.25(m, 2 H); MS (ES) m/z: 320.0 (MH⁺, 100%); HRMS Calcd. forC₂₀H₁₈NO₃(MH⁺): 320.1281. Found: 320.1278.

EXAMPLE 17 Benzoic acid 3-benzenesulfonylamino-4-benzyloxy-phenyl ester

[0368] To a stirred solution of benzoic acid 3-amino-4-benzyloxy-phenylester (5.91 g, 18.5 mmol) (which was obtained in Example 16) in ethylacetate (100 mL) and pyridine (20 mL) at 0° C. was added dropwise phenylsulfonyl chloride (3.26 g, 18.5 mmol) in 50 mL of ethyl acetate. Afterone hour at 0° C. the mixture was warmed to room temperature and stirredat room temperature over night. The reaction mixture was washed withwater and the organic layer was dried (MgSO₄) and concentrated.Recrystallization from CH₂Cl₂/hexanes gave the title compound as a whitesolid (4.65 g, 61%); ¹H NMR (300 MHz, CDCl₃) δ4.93(s, 2 H), 6.90-7.80(m,15 H), 8.12(d, J=8.5 Hz, 2 H), 9.81(s, 1 H); MS (ES) m/z: 458.9 (MH⁺,100%); HRMS Calcd. for C₂₆H₂₂NO₅S(MH⁺): 459.1141. Found: 459.1151.

EXAMPLE 18 Benzoic acid3-(benzenesulfonyl-benzyl-amino)-4-benzyloxy-phenyl ester

[0369] To a stirred solution of benzoic acid3-benzenesulfonylamino-4-benzyloxy-phenyl ester(which was obtained inExample 17) (2.88 g, 7.27 mmol) in DMF(20 mL) was added 60% sodiumhydride (0.32 g, 8 mmol). After hydrogen evolution had subsided thestirred mixture was heated at 70° C. for 15 minute, and then it wascooled down to room temperature and a solution of benzyl chloride (1.01g, 8 mmol) in 5 mL of DMF was added dropwise. The mixture was thenheated at 85-90° C. for 2 hours, then it was cooled down to roomtemperature, poured into ice-water. The aqueous layer was extracted withethyl acetate and the organic layer was dried and concentrated. Theproduct was purified by flash silica gel chromatography eluting withethyl acetate and hexanes to give the title compound as a white solid(2.40 g, 70%); ¹H NMR (300 MHz, CDCl₃) δ4.74(s, 2 H), 4.83(s, 2 H),8.83(d, J=8.9 Hz, 1 H), 8.10-8.50(m, 2 H); HRMS Calcd. forC₃₃H₂₈NO₅S(MH⁺): 550.1688. Found: 550.1680.

EXAMPLE 19 N-Benzyl-N-(2-benzyloxy-5-hydroxy-phenyl)-benzenesulfonamide

[0370] To a stirred solution of benzoic acid3-(benzenesulfonyl-benzyl-amino)-4-benzyloxy-phenyl ester (which wasobtained in Example 18) (1.80 g, 3.28 mmol) in THF (10 ml) and methanol(10 mL) was added 10% of sodium hydroxide (10 mL). The mixture wasstirred at room temperature for 1.5 hours, acidified, with concentratedhydrochloric acid and diluted with water (200 mL). The aqueous solutionwas extracted with CH₂Cl₂. The organic phase was dried over MgSO₄ andconcentrated. The product was purified by flash silica gelchromatography eluting with ethyl acetate and hexanes to give the titlecompound as a white solid (1.20 g, 82%); ¹H NMR (300 MHz, CDCl₃) δ4.71(brs, 4 H), 6.49(d, J=3.0 Hz, 1 H), 6.62(dd, J=9.0, 3.0 Hz, 1 H),6.84(d, J=9.0 Hz, 1 H), 7.10-7.70(m, 15 H), 9.07(brs, 1 H); MS (ES) m/z:444.0 ((M−H)⁻, 100%); HRMS Calcd. for C₂₆H₂₂NO₄S(M−H)⁻: 444.1275. Found:444.1270.

EXAMPLE 20N-Benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-benzenesulfonamide

[0371] The title compound was prepared fromN-benzyl-N-(2-benzyloxy-5-hydroxy-phenyl)-benzenesulfonamide (which wasobtained in Example 19 ) according to the procedure of Example 2 as awhite solid; ¹H NMR (300 MHz, CDCl₃) δ2.68(dd, J=4.9, 2.7 Hz, 1 H),2.85(t, J=4.7 Hz, 1 H), 3.20-3.30(m, 1 H), 3.76(dd, J=11.0, 5.7 Hz, 1H), 4.05(dd, J=11.0, 3.1 Hz, 1 H), 4.65(s, 2 H), 4.81(brs, 2 H),6.65-6.80(m, 3 H), 7.05-7.15(m, 2 H), 7.15-7.50(m, 11 H), 7.65-7.75(m, 2H); HRMS Calcd. for C₂₉H₂₈NO₅S(MH⁺): 502.1689. Found: 502.1675.

EXAMPLE 21N-[5-(3-Amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide

[0372] The title compound was prepared fromN-benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-benzenesulfonamide(which was obtained in Example 20) according to the procedure of Example12 as a brown solid; ¹H NMR (300 MHz, CDCl₃) δ3.40-4.20(m, 5 H),6.40-7.00(m, 3 H), 7.10-7.60(m, 3 H), 7.60-7.80(m, 2 H), 8.15(brs, 1 H);MS (ES) m/z: 338.8 (MH⁺, 100%); HRMS Calcd. for C₁₅H₁₉N₂O₅S(MH⁺):339.1009. Found: 339.1004.

EXAMPLE 22 5-Acetyl-2-chloro-phenylaniline

[0373] To a stirred solution of 4-chloro-3-nitroacetophenone (10 g, 50mmol) in concentracted hydrochloric acid (150 mL) was added tin chloridedihydrate (33.8 g, 150 mmol). The mixture was stirred at roomtemperature for one day, basified with 28% of ammonium hydroxide anddiluted with water (1 L). The aqueous solution was extracted withmethylene chloride. The organic phase was dried over MgSO₄ andconcentrated. Recrystallization from CH₂Cl₂/hexanes gave the titlecompound as a yellowish crystal (7.0 g, 83%); ¹H NMR (300 MHz, CDCl₃)δ2.55(s, 3 H), 4.19(brs, 2 H), 7.22-7.38(m, 3 H); MS (ES) m/z: 169.8(MH⁺, 100%); HRMS Calcd. for C₈H₉ClNO(MH⁺): 170.3667. Found: 170.0368.

EXAMPLE 23 N-(5-Acetyl-2-chloro-phenyl)-methanesulfonamide

[0374] To a stirred solution of 5-acetyl-2-chloro-phenylaniline (whichwas obtained in Example 22)(7.40 g, 43.5 mmol) in CH₂Cl₂(200 mL) andpyridine (40 mL) at 0˜5° C. was added dropwise methanesulfonyl chloride(5.0 g, 43.6 mmol) in 50 mL of CH₂Cl₂. After 1 hour at 0° C. the mixturewas warmed to room temperature and stirred at room temperature foranother hour. The solvents were removed and the residue was dissolved inCH₂Cl₂(500 mL). The reaction mixture was washed with water and theorganic layer was dried (MgSO₄) and concentrated. The product waspurified by flash silica gel chromatography eluting with ethyl acetateand hexanes to give the title compound as a white solid (6.1 g, 57%); ¹HNMR (300 MHz, DMSO-d₆) δ2.58(s, 3 H), 3.08(s, 3 H), 7.69(d, J=8.3 Hz, 1H), 7.83(dd, J=8.3, 2.1 Hz, 1 H), 7.94(d, J=2.1 Hz, 1 H), 9.69(s, 1 H);MS (ES) m/z: 245.9 ((M−H)⁻, 100%); HRMS Calcd. for C₉H₁₁ClNO₃S(MH⁺):248.0148. Found: 248.0135.

EXAMPLE 24 N-(5-Bromoacetyl-2-chloro-phenyl)-methanesulfonamide

[0375] A mixture of N-(5-acetyl-2-chloro-phenyl)-methanesulfonamide(2.47 g, 10 mmol) (which was obtained in Example 23) and copper(II)bromide (11.17 g, 50 mmol) in chloroform (150 mL) was refluxed for 5hours. After cooling down to room temperature the solid was filtered offand the solution was concentrated. Recrystallization fromchloroform/diethyl ether gave the title compound as a white solid (3.10g, 96%); ¹H NMR (300 MHz, CDCl₃) δ3.09(s, 3 H), 4.42(s, 2 H), 6.91 (brs,1 H), 7.58(d, J=8.4 Hz, 1 H), 7.77(dd, J=8.4, 2.1 Hz, 1 H), 8.24 (d,J=2.1 Hz, 1 H); MS (ES) m/z: 323.7 ((M−H)⁻, 100%); HRMS Calcd. forC₉H₁₀BrClNO₃S(MH⁺): 325.9249. Found: 325.9245.

EXAMPLE 25N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide

[0376] R-2-Methyl-CBS-oxazaborolidine (1.0 M in THF, 2 mL, 2 mmol) in 50mL of THF was added slowly to a stirred solution of borane-THF complex(1.0 M in THF, 12 mL, 12 mmol) at room temperature. The mixture wasstirred for 30 minutes and thenN-(5-bromoacetyl-2-chloro-phenyl)-methanesulfonamide (which was obtainedin Example 24)(2.80 g, 8.6 mmol) in 50 ml of THF was added dropwise.Upon stirring over night hydrochloride (1.0 M solution in diethyl ether)was added until the pH was ˜1. After stirring for one hour the reactionmixture was partitioned between ethyl acetate and water. The organicphase was dried over MgSO₄ and concentrated. The residue was thendissolved in 50 mL of DMSO. To the solution sodium azide (2.93 g, 45mmol) and sodium iodide (3 g, 20 mmol) were added. After stirring atroom temperature for 3 days the reaction was quenched with water,extracted with diethyl ether. The organic layer was dried over MgSO₄ andconcentrated. The product was purified by flash silica gelchromatography eluting with ethyl acetate and hexanes to give the titlecompound as a white solid (1.6 g, 64%); ¹H NMR (300 MHz, CDCl₃) δ2.60(d,J=5.9 Hz, 1 H), 3.06(s, 3 H), 3.45-3.50(m, 2 H), 4.85-4.95(m, 1 H),6.84(brs, 1 H), 7.22(dd, J=8.3, 2.0 Hz, 1 H), 7.44(d, J=8.3 Hz, 1 H),7.65 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 288.9 ((M−H)⁻, 100%); HRMS Calcd.for C₉H₁₂ClN₄O₃S(M⁺): 290.0241. Found: 290.0228.

EXAMPLE 26 Propane-2-sulfonic acid (5-acetyl-2-benzyloxy-phenyl)-amide

[0377] To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone(EP 0 659 737) (30 g, 125.0 mmol) in CH₂Cl₂(500 mL) and pyridine (250mL) was added dropwise isopropylsufonyl chloride (28.6, 200 mmol) atroom temperature. The reaction was stirred for 3 days under nitrogenatmosphere. The mixture was diluted with CH₂Cl₂(700 mL) and washed with1N hydrochloric acid, water, dried over Na₂SO₄, and concentrated. Theproduct was purified by flash silica gel chromatography eluting withethyl acetate/hexanes to give the title compound as a white solid (13 g,30%); ¹H NMR (300 MHz, CDCl₃) δ1.35(d, J=6.9 Hz, 6 H), 2.56(s, 3 H),3.25-3.45(m, 1 H), 5.18(s, 2 H), 6.75(brs, 1 H), 7.02 (d, J=8.6 Hz, 1H), 7.30-7.50(m, 5 H), 7.70(dd, J=8.6, 2.1 Hz, 1 H), 8.18 (d, J=2.1 Hz,1 H); MS (ES) m/z: 364.9 ((M+NH₄)⁺, 100%; HRMS Calcd. forC₁₈H₂₂NO₄S(MH⁺): 348.1264. Found: 348.1259.

EXAMPLE 27 Propane-2-sulfonic acid[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide

[0378] The title compound was prepared from propane-2-sulfonic acid(5-acetyl-2-benzyloxy-phenyl)-amide (which was obtained in Example 26)as described in the procedures of Example 25 and Example 10 as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ1.26(d, J=6.8 Hz, 6 H), 2.74 (dd,J=12.6, 9.8 Hz, 1 H), 2.92 (dd, J=12.6, 3.0 Hz, 1 H), 3.10-3.20(m, 1 H),4.63 (dd, J=9.8, 3.0 Hz, 1 H), 6.85(d, J=8.3 Hz, 1 H), 7.01 (dd, J=8.3,2.1 Hz, 1 H), 7.27 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 274.8 (MH⁺, 100%);HRMS Calcd. for C₁₁H₁₈N₂O₄S(MH⁺): 274.0987. Found: 274.1004.

EXAMPLE 28 N-(5-Acetyl-2-benzyloxy-phenyl)-benzenesulfonamide

[0379] To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone(EP 0 659 737) (16.98 g, 70.0 mmol) in pyridine (50 mL) was addeddropwise benzenesulfonyl chloride (13.09 g, 73.5 mmol) in 100 mL ofpyridine at room temperature. The reaction was stirred for 18 hoursunder nitrogen atmosphere. The mixture was diluted with CH₂Cl₂ (700 mL)and washed with 1N hydrochloric acid, water, dried over Na₂SO₄, andconcentrated. The product was purified by flash silica gelchromatography eluting with CH₂Cl₂ to give the title compound as a tansolid (12.55 g, 47%); ¹H NMR (300 MHz, DMSO-d₆) δ3.33(s, 3 H), 5.03(s, 2H), 7.02(d, J=8.7 Hz, 1 H), 7.35(m, 3 H), 7.44(t, J=15 Hz, 2 H), 7.58(m,1 H), 7.50 (m, 3 H), 7.81(d, 1 H), 9.83(s, 1 H); MS (ES) m/z: 381.9(MH⁺, 100%); HRMS Calcd. for C₂₁H₁₉NO₄S(MH⁺): 382.1107. Found: 382.1100.

EXAMPLE 29 N-(2-Benzyloxy-5-bromoacetyl-phenyl)-benzenesulfonamide

[0380] A mixture of N-(5-acetyl-2-benzyloxy-phenyl)-benzenesulfonamide(which was obtained in Example 28) (1.0 g, 2.6 mmol) and copper (II)bromide (0.99 g, 4.4 mmol) in chloroform/ethyl acetate (45 ml) wasrefluxed under nitrogen atmosphere for 18 hours. Reaction mixture wasfiltered through celite and the filtrate was concentrated.Recrystallization from ethyl acetate gave the titled compound as a whitesolid (0.64 g, 53%); ¹H NMR (300 MHz, DMSO-d₆) δ4.79(s, 2 H), 5.06(s, 2H), 7.05(m, 1 H), 7.33(m, 5 H), 7.43(t, J=12 Hz, 2 H), 7.58(m, 1 H),7.69(d, J=3 Hz, 2 H), 7.86(m, 2 H) 9.89 (s, 1 H); MS (ES) m/z: 459.8(MH⁺, 85%); HRMS Calcd. for C₂₁H₁₈BrNO₄S(MH⁺): 460.0213. Found:460.0212.

EXAMPLE 30N-(2-Benzyloxy-5-(2-bromo-1-hydroxy-ethyl-phenyl)-benzenesulfonamide

[0381] R-2-Methyl-CBS-oxazaborolidine (1.0 M in THF, 0.54 mL, 0.54 mmol)was added slowly to to a stirred solution of borane-THF complex (1.0 Min THF, 3.23 ML, 3.23 mmol) at room temperature. The mixture was stirredfor an additional 20-30 minutes.N-(2-benzyloxy-5-bromoacetyl-phenyl)-benzenesulfonamide (which wasobtained in Example 29) (2.48 g, 5.4 mmol) in THF (40 mL) was addeddropwise to the mixture. The reaction was stirred an additional 18hours. The reaction was cooled to 0° C. and quenched with 1Nhydrochloric acid. The mixture was stirred at 0° C. for one hour. Themixture was partitioned between water and ethyl acetate, dried overMgSO₄, and concentrated. The product was purified by flash silica gelchromatography eluting with 1% methanol in CH₂Cl₂ to give the titledcompound (1.52 g, 61%); ¹H NMR (300 MHz, CDCl₃) δ2.56 (d, J=6 Hz, 1 H),3.53 (m, 2 H), 4.86 (s, 2 H); 6.77 (d, J=6 Hz, 1 H), 7.13 (m, 4 H), 7.35(m, 4 H), 7.53 (m, 1 H), 7.59 (d, J=2.1 Hz, 1 H), 7.69 (m, 2 H); MS (ES)m/z: 459.9 ((M−H)⁻, 100%); HRMS Calcd. for C₂₁H₂₀BrNO₄S(MH⁺): 462.0369.Found: 462.0366.

EXAMPLE 31N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl[-benzenesulfonamide

[0382] To a stirred solution ofN-(2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl-phenyl)-benzenesulfonamide(1.52 g, 3.3 mmol) which was obtained in Example 30) indimethylsultoxide under nitrogen atmosphere was added sodium iodide (0.5g, 3.3 mmol) and sodium azide (0.86 g, 13.2 mmol). The reaction wasstirred for three days at room temperature. The reaction mixture waspoured onto water, extracted with ethyl acetate three times, dried overmagnesium sulfate, and concentrated to give the titled compound as anoil; ¹H NMR (300 MHz, CDCl₃) δ3.43(m, 2 H), 4.79(m, 1 H), 4.86(s, 2 H),6.76(d, J=9 Hz, 1 H), 7.06(m, 2 H), 7.13(m, 2 H), 7.35(m, 4 H), 7.57(m,2 H), 7.69(d, J=9 Hz, 2 H).

EXAMPLE 32N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-benzenesulfonamide

[0383] A mixture ofN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-benzenesulfonamide(1.4 g, 3.3 mmol) which was obtained in Example 31), HCO₂NH₄(2.08 g, 3.3mmol), and 10% Pd/C in absolute ethanol (15 mL) under nitrogenatmosphere was heated under reflux for 2.5 hours. The mixture was cooledto room temperature, filtered through celite pad, and filtrateconcentrated and placed under high vacuum to give the titled compound asyellow solid (0.7 g, 69%); ¹H NMR (300 MHz, DMSO-d₆) δ2.74(d, J=15 Hz, 2H), 4.51 (d, J=6 Hz, 1 H), 6.63(d, J=9 Hz, 1 H), 6.76(d, J=9 Hz, 1 H),7.12(s, 1 H), 7.47(m, 4 H), 7.72(d, J=6 Hz, 2 H).

EXAMPLE 335-[4(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one

[0384] A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol),rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 mlof acetic acid(AcOh) was refluxed for 2 hours. The solid which wasformed on cooling the solution was collected to give the title compoundas a red solid (4.8 g, 66%); ¹H NMR (300 MHz, CDCl₃) δ1.81 (t, J=5.5 Hz,4 H), 3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H),7.58 (d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH⁺); HRMSCalcd. for C₁₇H₁₉N₂O₃S₂(MH⁺): 363.0837. Found: 363.0852. Anal. Calcd.for C₁₇H₁₈N₂O₃S₂: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89;N, 7.73.

EXAMPLE 341-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one

[0385]5-[4(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one(which was obtained in Example 33) (0.9 g, 2.5 mmol) was treated withconcentrated hydrochloric acid (25 mL) at room temperature. After 15hours ˜28% ammonium hydroxide (NH₄OH) was added dropwise and theprecipitate was collected by filtration, and dried over phosphoruspentoxide (P₂O₅) to give the title compound as a red solid (0.71 g,89%); ¹H NMR (300 MHz, DMSO-d₆) δ2.46 (t, J=6.1 Hz, 4 H), 3.79 (t, J=6.1Hz, 4 H), 7.11 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz, 2 H), 7.56 (s, 1H); MS (ES) m/z: 316.9 (M−H)⁻; HRMS Calcd. C₁₅H₁₄N₂O₂S₂(M⁺): 318.0497.Found: 31.8.0502.

EXAMPLE 355-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidenel-thiazolidine-2,4-dione

[0386] A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehydebenzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606)(15g, 60 mol), 2,4-thiazolidinedione (7.0 g, 60 mmol), and piperidine (8.0mL, 81.2 mmol) in 450 mL of ethanol was refluxed for 6 hours. The solidwhich was formed on cooling the solution was collected to give the titlecompound as an orange solid (20.5 g, 99%); ¹H NMR (300 MHz, DMSO-d₆)δ1.67 (t, J=5.6 Hz, 4 H), 3.47 (t, J=5.6 Hz, 4 H), 3.92 (s, 4 H), 7.07(d, J=9.0 Hz, 2 H), 7.43 (d, J=9.0 Hz, 2 H), 7.67 (s, 1 H), 12.40 (brs,1 H); MS (ES) m/z: 346.8 (MH⁺); HRMS Calcd. for C₁₇H₁₉N₂O₄S(MH⁺):346.0987. Found: 346.0994. Anal. Calcd. for C₁₇H₁₈N₂O₄S: C, 58.94; H,5.24; N, 8.09. Found: C, 58.92; H, 5.11; N, 7.96.

EXAMPLE 36 5-[4-(Oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione

[0387] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in example 35) according to the procedure of Example34 as an orange solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.45 (t, J=6.0 Hz, 4H), 3.76 (d, J=6.0 Hz, 4 H), 7.10 (d, J=9.0 Hz, 2 H), 7.48 (d, J=9.0 Hz,2 H), 7.70 (s, 1 H), 12.41 (brs, 1 H); MS (ES) m/z: 301.0 (M−H )⁻; HRMSCalcd. for C₁₅H₁₄N₂O₃S(M⁺): 302.0726. Found: 302.0731.

EXAMPLE 375-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzyl]-thiazolidine-2,4-dione

[0388] Method A: A solution of5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 35) (8.0 g, 23 mmol) in acetic acid (75mL) and THF (225 mL) was hydrogenated (40 psi hydrogen) in a Parr shakerover 10% Pd/C (8 g) over 4 days. The catalyst was removed by filtrationover celite and the solvent was evaporated. The product was purified byflash silica gel chromatography (hexanes/ethyl acetate) to give thetitle compound as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.68(t, J=5.6 Hz, 4 H), 2.76 (dd, J=14.1, 11.0 Hz, 1 H), 3.22 (t, J=5.6 Hz,4 H), 3.30 (dd, J=14.1, 3.8 Hz, 1 H), 3.91 (s, 4 H), 4.50 (dd, J=11.0,3.8 Hz, 1 H), 6.86 (d, J=8.7 Hz, 2 H), 7.04 (d, J=8.7 Hz, 2 H); MS (ES)m/z: 349.3 (MH⁺); HRMS Calcd. for C₁₇H₂₀N₂O₄S(M⁺): 348.1144. Found:348.1146. Anal. Calcd. for C₁₇H₂₀N₂O₄S: C, 58.60; H, 5.79; N, 8.04.Found: C, 58.42; H, 5.67; N, 7.86.

[0389] Method B: A mixture of5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazolidine-2,4-dione(9.0 g, 25.9 mmol) (which was obtained in Example 35) and 5% sodiummercury amalgam(Na—Hg) (46 g, 100 mmol) in water (70 mL) and THF (200mL) was stirred at room temperature overnight. The organic layer wasdecanted from mercury (Hg) and water. Evaporation of the solvent gavethe title compound as an off-white solid. The product was found to beidentical with that prepared by method A.

EXAMPLE 38 5-[4-(4-Oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione

[0390] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzyl]-thiazolidine-2,4-dione(which was obtained in Example 37) according to the procedure of Example34 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.40 (t, J=5.9 Hz,4 H), 3.01 (dd, J=14.1, 9.2 Hz, 1 H), 3.29 (dd, J=14.1, 4.2 Hz, 1 H),3.57 (t, J=5.9 Hz, 4 H), 4.86 (dd, J=9.2, 4.2 Hz, 1 H), 6.96 (d, J=8.6Hz, 2 H), 7.10 (d, J=8.6 Hz, 2 H); MS (ES) m/z: 304.8 (MH⁺, 100%), 609.0(2MH⁺, 100%), 914.1 (3MH⁺, 10%); HRMS Calcd. for C₁₅H₁₆N₂O₃S(M⁺):304.0881. Found: 304.0905. Anal. Calcd. for C₁₅H₁₆N₂O₃S: C, 59.19; H,5.36; N, 9.20. Found: C, 58.96; H, 5.16; N, 8.91.

EXAMPLE 395-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-imidazolizolidine-2,4-dione

[0391] The title compound was prepared from4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and hydantoinaccording to the procedure of Example 35 as an orange solid; ¹H NMR (300MHz, DMSO-d₆) δ1.68 (t, J=5.8 Hz, 4 H), 3.38 (t, J=5.8 Hz, 4 H), 3.91(s, 4 H), 6.34 (s, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.49 (d, J=8.7 Hz, 2H), 10.33 (brs, 1 H), 11.05 (brs, 1 H); MS (ES) m/z: 330.0 (MH⁺); HRMSCalcd. for C₁₇H₂₀N₃O₄(MH⁺): 330.1454. Found: 330.1477.

EXAMPLE 405-[4-(1,4-Dioxa-8-aza-spiro4.5]dec-8-yl)-benzyl]-imidazolizolidine-2,4-dione

[0392] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-imidazolizolidine-2,4-dione(which was obtained in Example 39) according to the procedure of Example37 as an orange solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.68 (t, J=5.7 Hz, 4H), 2.56 (dd, J=13.9, 6.8 Hz, 1 H), 2.81 (dd, J=13.9, 4.1 Hz, 1 H), 3.16(t, J=5.7 Hz, 4 H), 3.74-3.85 (m, 1 H), 3.90 (s, 4 H), 6.82 (d, J=8.7Hz, 2 H), 6.96 (d, J=8.7 Hz, 2 H), 8.32 (s, 2 H); MS (ES) m/z: 331.9(MH⁺); HRMS Calcd. for C₁₇H₂₂N₃O₄(MH⁺): 332.1610. Found: 332.1639.

EXAMPLE 415-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-imino-thiazolidin-4-one

[0393] The title compound was prepared from4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde benzaldehyde(Taylor, E. C., Strotnicki, J. S. Synthesis, 1981, 606) andpseudothiohydantoin according to the procedure of Example 35 as anorange solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.68 (t, J=5.6 Hz, 4 H), 3.43(t, J=5.6 Hz, 4 H), 3.91 (s, 4 H), 7.06 (d, J=8.9 Hz, 2 H), 7.41 (d,J=8.9 Hz, 2 H), 7.48 (s, 1 H), 8.99 (brs, 1 H), 9.33 (brs, 1 H); MS (ES)m/z: 345.9 (MH⁺); HRMS Calcd. for C₁₇H₂₀N₃O₃S (MH⁺): 346.1226. Found:346.1205. Anal. Calcd. for C₁₇H₁₉N₃O₃S: C, 59.11; H, 5.54; N, 12.16.Found: C, 58.80; H, 5.71; N, 12.38.

EXAMPLE 425-[4-(4-Oxo-piperidin-1-yl)-benzylidene}-imidazolidine-2,4-dione

[0394] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-imidazolizolidine-2,4-dione(whichwas obtained in Example 39) according to the procedure of Example 34 asa yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.43 (t, J=6.0 Hz, 4 H),3.70 (t, J=6.0 Hz, 4 H), 6.36 (s, 1 H), 7.01 (d, J=9.0 Hz, 2 H), 7.53(d, J=9.0 Hz, 2 H), 10.35 (brs, 1 H), 11.10 (brs, 1 H); MS (ES) m/z:285.9 (MH⁺); HRMS Calcd. for C₁₅H₁₆N₃O₃ (MH⁺): 286.1192. Found:286.1169.

EXAMPLE 431-[4-(2-Imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one

[0395] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-imino-thiazolidin-4-one(which was obtained in Example 41) according to the procedure of Example34 as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.44 (t, J=6.0 Hz, 4H), 3.74 (t, J=6.0 Hz, 4 H), 7.14 (d, J=6.7 Hz, 2 H), 7.46 (d, J=6.7 Hz,2 H), 7.50 (s, 1 H), 9.00 (brs, 1 H), 9.24 (brs, 1 H); MS (ES) m/z:301.9 (MH⁺).

EXAMPLE 44 5-[4-(4-Oxo-piperidin-1-yl)-benzyl]-imidazolidine-2,4-dione

[0396] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzyl]-imidazolidine-2,4-dione(which was obtained in example 40) according to the procedure of Example34 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.39 (t, J=6.0 Hz,4 H), 2.83 (d, J=4.8 Hz, 2 H), 3.55 (t, J=6.0 Hz, 4 H), 4.25 (t, J=4.8Hz, 1 H), 6.92 (d, J=8.7 Hz, 2 H), 7.05 (d, J=8.7 Hz, 2 H), 7.91 (s, 1H); MS (ES) m/z: 287.9 (MH⁺); HRMS Calcd. for C₁₅H₁₈N₃O₃(MH⁺): 288.1348.Found: 288.1396.

EXAMPLE 451-[4-(2-Imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one

[0397] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-imino-thiazolidin-4-one(which was obtained in Example 41) according to the procedures ofExample 37 and Example 34 as a yellowish solid; ¹H NMR (300 MHz,DMSO-d₆) δ2.40 (t, J=5.9 Hz, 4 H), 2.79 (dd, J=14.2, 9.7 Hz, 1 H), 3.28(dd, J=14.2, 4.0 Hz, 1 H), 3.56 (t, J=5.9 Hz, 4 H), 4.54 (dd, J=9.7, 4.0Hz, 1 H), 6.92 (d, J=8.6 Hz, 2 H), 7.10 (d, J=8.6 Hz, 2 H), 8.68 (brs, 1H), 8.90 (brs, 1 H); MS (ES) m/z: 303.9 (MH⁺); HRMS Calcd. forC₁₅H₁₈N₃O_(s)S (MH⁺): 304.1119. Found: 304.1113.

EXAMPLE 468-[4-(1H-Tetrazol-5-yl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane

[0398] A mixture of 4-(1,4-dioxa-8-azaspiro(4.5)dec-8-yl)benzonitrilebenzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606)(10mmol, 2.44 g), sodium azide (30 mmol, 1.95 g) and triethylaminehydrochloride (30 mmol, 4.13 g) in toluene was heated to ˜95° C. overnight (Koguro, K., Oga, T., Missui, S. and Orita, R. Synthesis, 1998,910). After cooling the mixture was poured into water and the solidwhich was formed was collected. To the aqueous layer 36% hydrochloricacid was added dropwise to salt out more solid. The combined solids weredried to yield the title compound as an off-white solid (2.30 g, 80%);¹H NMR (300 MHz, DMSO-d₆) δ1.70 (t, J=5.7 Hz, 4 H), 3.44 (t, J=5.7 Hz, 4H), 3.92(s, 4 H), 7.12(d, J=9.0 Hz, 2 H), 7.85(d, J=9.0 Hz, 2 H); MS(ES) m/z: 288.4 (MH⁺); HRMS Calcd. for C₁₄H₁₇N₅O(M⁺): 287.1382. Found:287.1375.

EXAMPLE 47 1-[4-(1H-Tetrazol-5-yl)-phenyl]-piperidin-4-one

[0399] The title compound was prepared from8-[4-(1H-tetrazol-5-yl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane (whichwas obtained in Example 46) according to the procedures of Example 34 asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.45 (t, J=6.0 Hz, 4 H), 3.75(t, J=6.0 Hz, 4 H), 7.18(d, J=9.0 Hz, 2 H), 7.91 (d, J=9.0 Hz, 2 H); MS(ES) m/z: 244.0 (MH⁺); HRMS Calcd. for C₁₂H₁₃N₅O(M⁺): 243.1120. Found:243.1120.

EXAMPLE 48 Ethyl{5-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetateandethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate

[0400] To a solution of8-[4-(1H-tetrazol-5-yl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane (0.57g, 2 mmol) (which was obtained in Example 46) in DMF (10 mL) was addedcesium carbonate (0.81 g, 2.5 mmol) and ethyl iodoacetate (0.43 g, 2mmol). The mixture was stirred at room temperature over night, then thereaction was quenched with water, extracted with ethyl acetate. Theproducts from the organic phase was seperated by silica gelchromatography (ethyl acetate/hexanes) to yieldethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8yl)phenyl]-2H-tetraazol-2-yl}acetateas a colorless crystal (0.55 g, 73%) andethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetateas a gum (0.12 g, 16%).

[0401]Ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate:¹H NMR (300 MHz, CDCl₃) δ1.23(t, J=7.1 Hz, 3 H), 1.84 (t, J=5.8 Hz, 4H), 3.45 (t, J=5.8 Hz, 4 H), 4.00(s, 4 H), 4.28 (q, J=7.1 Hz, 2 H),5.42(s, 2 H), 7.01(d, J=9.0 Hz, 2 H), 8.02 (d, J=9.0 Hz, 2 H); MS (ES)m/z: 374.3 (MH⁺); HRMS Calcd. for C₁₈H₂₃N₅O₄(M⁺): 373.1750. Found:373.1750.

[0402]Ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate:¹H NMR (300 MHz, CDCl₃) δ1.26(t, J=7.1 Hz, 3 H), 1.79 (t, J=5.7 Hz, 4H), 3.49 (t, J=5.7 Hz, 4 H), 4.00(s, 4 H), 4.26 (q, J=7.1 Hz, 2 H),5.19(s, 2 H), 7.00(d, J=8.7 Hz, 2 H), 7.54 (d, J=8.7 Hz, 2 H); MS (ES)m/z: 374.3 (MH⁺); HRMS Calcd. for C₁₈H₂₃N₅O₄(M⁺): 373.1750. Found:373.176.1.

EXAMPLE 49 tert-Butyl2-{2,4-dioxo-5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidin-3-yl}acetate

[0403] Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was addedinto a mixture of5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg,1.65 mmol)(which was obtained in Example 38), and DMF. The mixture wasstirred for 1 hour at room temperature, and then tert-butyl bromoacetate(0.36 mL, 2.47 mmol) was added. The new mixture was stirred for 30minutes, poured into water, and extracted with ethyl acetate. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography (hexanes/ethyl acetate 3/1) gave a viscous oil (525mg, 76% yield); ¹H NMR (300 MHz, DMSO-d₆) δ1.40 (s, 9 H), 2.40 (m, 4H),2.9 (m, 1H), 3.45 (m, 1H), 3.56 (m, 4H), 4.20 (s, 2H), 5.05 (m, 1H),6.97 (m, 2H), 7.18 (m, 2H); MS (ES) m/z: 419 (MH⁺); Anal. Calcd. forC₁₅H₁₆N₂O₃S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.21; H, 6.44; N,6.52.

EXAMPLE 50 Ethyl2-{2,4-dioxo-5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidin-3-yl]acetate

[0404] Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was addedinto a mixture of5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg,1.65 mmol) (which was obtained in Example 38) and DMF. The mixture wasstirred for one hour at room temperature, and then ethyl bromoacetate(0.27. mL, 2.47 mmol) was added. The new mixture was stirred for 30minutes, poured into water, and extracted with ethyl acetate. Theorganic extracts were dried over MgSO₄. Evaporation and purification byflash chromatography (hexanes/ethyl acetate 2/1) gave a viscous oil (295mg, 46% yield); ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, J=7.16 Hz, 3H), 2.40(m, 4H), 2.95-3.00 (m, 1H), 3.4 (m, 1H), 3.60 (m, 2H), 4.10 (q, J=7.16Hz, 2H), 4.30 (s, 2H), 6.97 (m, 2H), 7.16 (m, 2H); MS (ES) m/z: 391(MH⁺);

EXAMPLE 51 4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde oxime

[0405] A solution of sodium acetate (6.64 g, 60.72 mmol) in water (10mL) was added into a mixture of4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde (5.0 g, 20.24 mmol)benzaldehyde (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606),hydroxylamine hydrochloride (4.22 g, 60.72 mmol), ethyl alcohol (300mL), and water (50 mL). The mixture: was stirred at 70° C. for 10 hours,then poured into water and extracted with ethyl acetate. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography (hexanes/ethyl acetate 2/1) gave a white solid (6.3 g,90% yield); mp 151-152° C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.63 (m, 4H),3.35 (m, 4H), 3.90 (s, 4H), 6.96 (m, 2H), 7.40 (m, 2H), 7.96 (s, 1H),10.75 (s, 1H); MS (ES) m/z: 263 (MH⁺); Anal. Calcd. for C₁₄H₁₈N₂O₃: C,64.11; H, 6.92; N, 10.68. Found: C, 64.24; H, 6.81; N, 10.64.

EXAMPLE 528-{4-[(Hydroxyamino)methyl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane

[0406] Hydrochloric acid (4N, in dioxane) was added dropwise into amixture of 4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzaldehyde oxime (5.3g, 20.24 mmol) (which was obtained in Example 51), sodiumcyanoborohydride (6.3 g, 101.2 mmol), methyl alcohol(200 mL), and methylorange (10 mg), until an acidic solution (pH about 4) was achieved. Themixture was then stirred for 1 hour, poured into water, neutralized withNaOH (2N) and extracted with ethyl acetate. The organic extracts weredried over MgSO₄. Evaporation and purification by flash chromatography(hexanes/ethyl acetate/methyl alcohol 10/5/1) gave a white solid (4.2 g,78% yield); mp 107-109° C. ¹H NMR (400 MHz, DMSO-d₆) δ1.64 (m, 4H), 3.20(m, 4H), 3.74 (s, 2H), 3.90 (s, 4H), 5.84 (brs, 1H), 6.86 (m, 2H), 7.14(m, 2H), 7.19 (brs, 1H); MS (ES) m/z: 265 (MH⁺).

EXAMPLE 53 N-[4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-N-hydroxyurea

[0407] Trimethylsilyl isocyanate (2.1 mL, 14.85 mmol) was added dropwiseinto a mixture of8-{4-[(hydroxyamino)methyl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane (2.61g, 9.9 mmol) (which was obtained in Example 52), THF(20 mL) and dioxane(20 mL). The mixture was stirred at room temperature for 24 hours,poured into water and extracted with ethyl acetate. The organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography (hexanes/ethyl acetate/methyl alcohol 10/5/1) gave awhite solid (2.2 g, 73% yield); mp 153-154° C.; ¹H NMR (400 MHz,DMSO-d₆) δ1.70 (m, 4H), 3.21 (m, 4H), 3.89 (s, 4H), 4.37 (s, 2H), 6.23(brs, 2H), 6.86 (m, 2H), 7.10 (m, 2H), 9.19 (s, 1H); MS (ES) m/z: 308(MH⁺); Anal. Calcd. for C₁₅H₂₁N₃O₄: C, 58.62; H, 6.89; N, 13.67. Found:C, 58.37; H, 6.78; N, 13.47

EXAMPLE 54 N-Hydroxy-N-[4-(4-oxo-1-piperidinyl)benzyl]urea

[0408] A mixture ofN-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzyl]-N-hydroxyurea (2.2 g,7.16 mmol) (which was obtained in Example 53) and hydrochloric acid(concentrated, 10 mL) was stirred at room temperature for three days.The mixture was then neutralized with ammonium hydroxide, and extractedwith ethyl acetate. The organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography (ethyl acetate)gave a white solid (1.86 g, 98% yield); mp 138-140° C.; ¹H NMR (300 MHz,DMSO-d₆) δ2.41 (m, 4H), 3.60 (m, 4H), 4.43 (s, 2H), 6.37 (brs, 2H), 7.03(m, 2H), 7.21 (m, 2H), 9.31 (s, 1H); MS (ES) m/z: 264 (MH⁺);

EXAMPLE 552-[4-(4-Oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione

[0409] Sodium hydride (60% in mineral oil, 456 mg, 11.4 mmol) was addedinto a mixture of N-hydroxy-N-[4-(4-oxo-1-piperidinyl)benzyl]urea (1.5g, 5.7 mmol) (which was obtained in Example 54), and THF(10 mL). Themixture was stirred at room temperature for 2 hours, and then methylchloroformate (2.0 mL, 22.8 mmol) was added. The new mixture was stirredfor 2 hours, poured into water, acidified with hydrochloric acid (2 N)to pH about 6, and extracted with ethyl acetate. The organic extractswere dried over MgSO₄. Evaporation gave a yellow solid (1.58 g). Part ofthose material (460 mg, 1.43 mmol) was taken in DMF (4 mL) and treatedwith sodium hydride (60% in mineral oil, 57.3 mg, 1.43 mmol). Themixture was stirred for 1 hour, poured into water, acidified withhydrochloric acid (2N) and extracted with ethyl acetate. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography (hexanes/ethyl acetate 1/1) gave the title compound as ayellow solid (3.55 g, 85% yield); ¹H NMR (300 MHz, DMSO-d₆) δ2.42 (m,4H), 3.62 (m, 4H), 4.76 (s, 2H), 7.1 (m, 2H), 7.23 (m, 2H), 12.43 (brs,1H); MS (ES) m/z: 290 (MH⁺).

EXAMPLE 56 3-Bromo-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde

[0410] A mixture of 1,4-dioxa-8-azaspiro[4.5]decane (6.87 g, 48 mmol),3-bromo-4-fluorobenzaldehyde(8.12 g, 40 mmol), and potassium carbonate(6.63 g, 48 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(12 mL) and acetonitrile (8 mL) was heated at 80° C. under N₂ atmospherefor one day. Reaction mixture was cooled down to room temperature andpoured onto water (150 mL). The mixture was extracted with methylenechloride. The organic layer was dried (MgSO₄) and concentrated to givethe title compound as an off-white solid (12.4 g, 96%); mp 63-64° C.; ¹HNMR (300 MHz, CDCl₃) δ1.93 (t, J=5.7 Hz, 4H), 3.25 (t, J=5.4 Hz, 4H);4.02 (s, 4H), 7.12 (d, J=4.2 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 2H), 8.06(d, J=1.8 Hz, 1H), 9.84 (s, 1H); MS (ES) m/z: 325.7 (MH⁺); HRMS Calcd.for C₁₄H₁₆BrNO₃ (MH⁺): 325.0314. Found: 325.0288.

EXAMPLE 575-[3-Bromo-4-(1,4-dioxa-8-aza-spiro[4.51]dec-8-yl)-benzylidene]-thiazolidine-2,4-dione

[0411] The title compound was prepared from3-bromo-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde(which wasobtained in Example 56), 2,4-thiazolidinedione and β-alanine accordingto the procedure of Example 33 as a yellow solid; mp 109-111° C.; ¹H NMR(300 MHz, DMSO-d₆) δ1.79 (t, J=5.1 Hz, 4H), 3.12 (m, 4H), 3.93 (s, 4H),6.87 (d, J=8.7 Hz, 1H), 7.52-7.55 (m, 1H), 7.61 (s, 1H), 7.83-7.87 (m,1H), 12.5 (s, 1H); MS (ES) m/z: 425.1 (MH⁺).

EXAMPLE 585-[3-Bromo-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione

[0412] The title compound was prepared from5-[3-bromo-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 57) according to the procedure of Example34 as a yellow solid; mp>210° C.; ¹H NMR (300 MHz, DMSO-d₆) δ2.54 (t,J=4.5 Hz, 4H), 3.37 (t, J=4.5 Hz, 4H), 7.32 (d, J=6.3 Hz, 1H), 7.56 (dd,J=6.3, 1.5 Hz, 1H), 7.74 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 12.6 (s, 1H);MS (ES) m/z: 380.8 (MH⁺); HRMS Calcd. for C₁₅H₁₄BrN₂O₃S(MH⁺): 380.9909.Found: 380.9874.

EXAMPLE 59 4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzaldehyde

[0413] The title compound was prepared from, 1,4dioxa-8-azaspiro[4.5]decane and 3,4-difluorobenzaldehyde according tothe procedure of Example 56 as an orange oil; ¹H NMR (300 MHz, CDCl₃)δ1.88 (t, J=5.7 Hz, 4H), 3.35 (t, J=5.8 Hz, 4H), 4.01 (s, 4H), 6.96 (t,J=7.8 Hz, 1H), 7.47-7.49 (m, 1H), 7.53-7.58 (m, 1H), 9.81 (s, 1H); MS(ES) m/z: 265.8 (MH⁺).

EXAMPLE 605-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzylidene]-thiazolidine-2,4-dione

[0414] The title compound was prepard from4-(1,4-dioxa-8-aza-spiro[4.5]dec -8-yl)-3-fluoro-benzaldehyde (which wasobtained in Example 59), 2,4 thiazolidinedione and β-alanine accordingto the procedure of Example 33 as an orange solid; mp 159-160° C.; ¹HNMR (300 MHz, CDCl₃) δ7.01 (m, 1H), 7.13-7.22 (m, 2H), 7.71-7.77 (m,1H); MS (ES) m/z: 363.3 (M−H)⁻.

EXAMPLE 615-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione

[0415] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 60) according to the procedures ofExample 37 and Example 34 as a yellow solid; mp 129-130° C.; ¹H NMR (300MHz, CDCl₃) δ2.62 (t, J=6.0 Hz, 4H), 3.09-3.19 (m, 2H), 3.40 (t, J=6.0Hz, 4H), 4.47-4.54 (m, 1H), 6.88-7.00 (m, 3H), 8.22 (brs, 1H); MS (ES)m/z: 322.9 (MH⁺); HRMS Calcd. for C₁₅H₁₆FN₂O₃S (MH⁺): 323.0865. Found:323.0837.

EXAMPLE 625-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione

[0416] The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 60) according to the procedure of Example34 as a yellow solid; mp>200° C.; ¹H NMR (300 MHz, DMSO-d₆) δ2.51 (m,4H), 3.54 (t, J=5.97 Hz, 4H), 7.24-7.30 (m, 1H), 7.31-7.49 (m, 2H), 7.73(s, 1H), 12.5 (s, 1H); MS (ES) m/z: 319.0 (M−H)⁻; HRMS Calcd. forC₁₅H₁₄FN₂O₃S(MH⁺): 321.0709. Found: 321.0712

EXAMPLE 63N-[5-((1R)-2-{1-[4-(3,5-Dioxo-[1,2,4]oxadiazolidin-2-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0417] Acetic acid (0.09 mL, 1.6 mmol) was added to a mixture ofN-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide(197 mg, 0.8 mmol) (which was obtained in Example 10),2-[4-(4-oxo-1-piperidinyl)benzyl]-1,2,4-oxadiazolidine-3,5-dione (231mg, 0.8 mmol) (which was obtained in Example 55), and DMF(5 mL). Themixture was stirred for 20 minutes and then, sodiumtriacetoxyborohydride (203 mg, 0.96 mmol) was added, and the new mixturewas stirred at room temperature for 24 hours. The volatiles were removedin vacuo and the residue was purified by flash chromatography(dichloromethane/methyl alcohol 4/1) to produce an off-white solid (296mg, 71% yield); mp 193-195° C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.58-1.62 (m,2H), 1.96-2.07 (m, 2H), 2.60-2.70 (m, 2H), 2.86-3.17 (m, 6H), 3.72-3.8(m, 2H), 4.28 (s, 2H), 2.70-2.74 (m, 1H), 6.83-6.87 (m, 3H), 7.03-7.13(m, 3H), 7.23 (m, 1H), 8.60 (brs, 2H); MS (ES) m/z: 518 (M−H)⁻.

EXAMPLE 645-[[4-[4-[[(R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid tert-butyl-ester

[0418] Acetic acid (0.12 mL, 2.16 mmol) was added to a mixture ofN-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide(266 mg, 1.08 mmol) (which was obtained in Example 10), tert-butyl2-{2,4-dioxo-5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidin-3-yl}acetate(450 mg, 1.08 mmol) (which was obtained in Example 49), and DMF (5 mL).The mixture was stirred for 20 minutes and then, sodiumtriacetoxyborohydride (276 mg, 1.3 mmol) was added, and the new mixturewas stirred at room temperature for 24 hours. The volatiles were removedin vacuo and the residue was purified by flash chromatography(dichloromethane/methyl alcohol 5/1) to produce a yellow solid (480 mg,68% yield); mp 130-132° C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.20-1.50 (m, 11H), 1.81-1.85 (m, 2H), 2.60-2.80 (m, 4H), 2.85-2.9 (m, 4H), 3.40 (m,1H), 3.60 (m, 1H), 4.20 (s, 2H), 4.50 (m, 1H), 5.04 (m, 1H), 6.80-6.87(m, 3H), 7.02 (m, 1H), 7.08 (m, 2H), 7.20 (m, 1H); Anal. Calcd. forC₃₀H₄₀N₄O₈S₂: C, 55.54; H; 6.21; N, 8.64. Found: C, 53.86; H, 6.11; N,7.65.

EXAMPLE 655-[[4-[4-[[(R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsufonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid

[0419] A mixture of5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]-phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid tert-butyl-ester (300 mg, 0.46 mmol) (which was obtained in Example64), dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) wasstirred at room temperature for 10 hours. The mixture was then pouredinto ethyl ether (50 mL), and the precipitated solid was filtered anddried to give an off-white solid (189 mg, 58% yield); mp 158-160° C.; ¹HNMR (400 MHz, DMSO-d₆) δ1.58-1.66 (m, 2H), 2.02-2.10 (m, 2H), 2.60-2.64(m, 2H), 2.85-3.04 (m, 4H), 3.16-3.40 (m, 4H), 3.80 (m, 2H), 4.20 (s,2H), 4.80 (m, 1H), 5.06 (m, 1H), 6.17 (brs, 1H), 6.87-6.91 (m, 3H),7.05-7.1 (m, 3H), 7.23 (m, 1H), 8.60 (brs, 1H), 8.80 (s, 1H), 9.94 (s,1H), 13.3 (brs, 1H); MS (ES) m/z: 649 (MH⁺).

EXAMPLE 665-[[4-[4-[[(R)-2-Hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid ethyl-ester

[0420] Acetic acid (0.05 mL, 0.92 mmol) was added to a mixture ofN-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide(whichwas obtained in Example 10) (113 mg, 0.46 mmol), ethyl2-{2,4-dioxo-5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidin-3-yl}acetate(which was obtained in Example 50) (180 mg, 0.46 mmol), and DMF (3 mL).The mixture was stirred for 20 minutes and then, sodiumtriacetoxyborohydride (117 mg, 0.55 mmol) was added, and the new mixturewas stirred at room temperature for 24 hours. The volatiles were removedin vacuo and the residue was purified by flash chromatography(dichloromethane/methyl alcohol 5/1) to produce an off-white solid (210mg, 74% yield); mp 153-155° C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.18 (t,J=7.1 Hz, 3H), 1.30-1.60 (m, 2H), 1.80-1.83 (m, 2H), 2.50-2.65 (m, 4H),2.80-2.85 (m, 4H), 3.40 (m, 2H), 3.60 (m, 1H), 4.13 (q, J=7.1 Hz, 2H),4.47 (m, 1H), 5.04 (m, 1H), 6.80-6.90 (m, 3H), 6.97 (m, 1H), 7.1 (m,2H), 7.19 (m, 1H); MS (ES) m/z: 621 (MH⁺); Anal. Calcd. for:C₂₈H₃₆N₄O₈S₂×1 CH₃CO₂H: C, 52.93; H, 5.92; N, 8.23. Found: C, 53.69; H,5.63; N, 8.23.

EXAMPLE 675-(3-Fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0421] The title compound was prepared from4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S.Pat. No. 5,786,356/1998) and5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione(which was obtained in Example 61) according to the procedure of Example63 as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.56-1.62 (m, 2H),2.04 (m, 2H), 2.63-2.75 (m, 5H), 2.86-2.95 (m, 4H), 3.01-3.10 (m, 4H),4.50-4.55 (m, 1H), 5.33 (brs, 1H), 6.57-6.65 (m, 2H), 6.84-7.09 (m, 3H),8.22 (s, 1H), 7.22-7.29 (m, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES)m/z: 530.0 (MH⁺); HRMS Calcd. for C₂₅H₂₉FN₅O₅S (MH⁺): 530.1873. Found:530.1876.

EXAMPLE 685-(3-Bromo-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione

[0422] The title compound was prepared from4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S.Pat. No. 5,786,356/1998) and5-[3-bromo-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 58) according to the procedure of Example63 as an olive green solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.66-1.77 (m,4H), 2.10-2.19 (m, 4H), 2.68-2.76 (m, 2H), 3.07-3.14 (m, 3H), 3.99-4.09(m, 2H), 5.62 (brs, 1H), 6.58-6.66 (m, 2H), 6.88 (t, J=8.1 Hz, 1H),7.20-7.25 (m, 3H), 7.50 (dd, J=8.5, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H),10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 589.9 (MH⁺).

EXAMPLE 695-(3-Fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione

[0423] The title compound was prepared from4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S.Pat. No. 5,786,356/1998) and5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 62) according to the procedure of Example63 as an olive green solid; mp 162-164° C.; ¹H NMR (300 MHz, DMSO-d₆)δ1.66-1.74 (m, 2H), 2.07-2.17 (m, 2H), 2.74-2.83 (m, 2H), 3.12-3.15 (m,2H), 3.43-3.48 (m, 1H), 3.52-3.56 (m, 2H), 3.98-4.11 (m, 1H), 5.63 (brs,1H), 6.62 (m, 2H), 6.87 (t, J=8.1 Hz, 1H), 7.18 (t, J=9.1 Hz, 3H),7.27-7.35 (m, 1H), 10.60 (s, 1H), 10.7 (s, 1H); MS (ES) m/z: 527.9(MH⁺); HRMS Calcd. for C₂₅H₂₈FN₅O₅S (MH⁺): 528.1716. Found: 528.1702.

EXAMPLE 70N-[5-(2-{1-[2-Bromo-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0424] The title compound was prepared fromN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) and5-[3-bromo-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 58) according to the procedure of Example63 as a dull yellow solid; mp>200° C.; ¹H NMR (300 MHz, DMSO-d₆)δ1.70-1.82 (m, 2H), 2.07-2.17 (m, 2H), 2.65-2.73 (m, 3H), 2.95 (s, 3H),3.07-3.17 (m, 4H), 4.74-4.77 (m, 3H), 6.00 (brs, 1H), 6.89 (d, J=8.3 Hz,1H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.26-7.27 (m,2H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 8.7 (brs,1H), 9.9 (brs, 1H); MS (ES) m/z: 612.8 (MH⁺).

EXAMPLE 71N-[5-(2-{1-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0425] The title compound was prepared fromN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) and5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione(which was obtained in Example 62) according to the procedure of Example63 as a yellow solid; mp>225° C.; ¹H NMR (300 MHz, DMSO-d₆) δ1.62-1.71(m, 2H), 2.03-2.12 (m, 2H), 2.70-2.83 (m, 3H), 2.95 (s, 3H), 3.12-3.33(m, 2H), 3.49-3.52 (m, 2H), 4.72-4.75 (m 1H), 5.96 (brs, 1H), 6.89 (d,J=8.1 Hz, 1H), 7.05-7.13 (m, 3H), 7.25-7.38 (m, 3H), 8.70 (brs, 1H), 9.8(brs, 1H); MS (ES) m/z: 551.0 (MH⁺); HRMS for C₂₄H₂₇FN₄O₆S₂ (MH⁺):551.1434. Found: 551.1438.

EXAMPLE 725-{4-[4-((2S)-2-Hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-thioxo-thiazolidin-4-one

[0426]1-[4-(4-Oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Example 34) (0.16 g, 0.5 mmol) and(2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3)(0.12 g, 0.75 mmol) were mixed in 1,2-dichloroethane (10 mL) and thentreated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and aceticacid (0.045 g, 0.75 mmol). After stirring at room temperature under anitrogen atmosphere for one day the mixture was quenched with 1N sodiumhydroxide (NaOH) and then poured into a saturated aqueous sodiumbicarbonate (NaHCO₃). The aqueous layer was extracted withdichloromethane and the combined organic layers were dried andconcentrated. The residue was purified by preparative thin layerchromatography (16% MeOH/CH₂CH₂) to give the title compound as a paleyellowish solid; mp>220° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.50-1.70 (m, 2 H), 1.90-2.10 (m, 2 H), 2.60-3.40 (m, 7 H), 3.90-4.20(m, 3 H), 6.70-7.15 (m, 6 H), 7.30 (d, J=8.8 Hz, 2 H); 7.38 (d, J=8.8Hz, 2 H); MS (ES) m/z: 470.0 (MH⁺); HRMS Calcd. for C₂₄H₂₇N₃O₃S₂(M⁺):469.1494. Found: 469.1488.

EXAMPLE 735-[4-[4-((2S)-2-Hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzyl}-thiazolidin-2,4-dione

[0427] 5-{4-(4-Oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (whichwas obtained in Example 38) (0.15 g, 0.5 mmol) and(2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3)(0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and thentreated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and aceticacid (0.045 g, 0.75 mmol). After stirring at room temperature under anitrogen atmosphere for one day the mixture was quenched with 1N NaOHand then poured into a saturated aqueous NaHCO₃. The aqueous solutionwas extracted with 1-butanol and the combined organic layers wereconcentrated. The residue was purified by preparative thin layerchromatography (10% MeOH/CH₂CH₂) to give the title compound as a paleyellowish solid; mp 218-220° C.; ¹H NMR (300 MHz, DMSO-d₆) δ1.30-1.60(m, 2 H), 1.80-2.00 (m, 2 H), 2.50-3.00 (m, 5 H), 3.00-3.50 (m, 3 H),3.50-3.70 (m, 2 H), 3.85-4.00 (m, 3 H), 4.48 (dd, J=9.8, 3.8 Hz, 1 H),6.85 (d, J=8.6 Hz, 2 H), 6.90-6.97 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H),7.25-7.38 (m, 3 H); MS (ES) m/z: 456.0 (MH⁺); HRMS Calcd. forC₂₄H₂₉N₃O₄S (M⁺): 455.1878. Found: 455.1880.

EXAMPLE 745-(4-{4-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidin-1-}-benzyl)-thiazolidine-2,4-dione

[0428] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione(which wasobtained in Example 38) and(2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained inExample 4) according to the procedure of Example 73 as a pale yellowishsolid; mp>70° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.45-1.60 (m,2 H), 1.90-2.15 (m, 2 H), 2.67 (brt, J=11.7 Hz, 2 H), 2.75-3.05 (m, 4H), 3.26 (dd, J=14.1, 3.9 Hz, 1 H), 3.60-3.75 (m, 2 H), 3.80-3.95 (m, 2H), 3.95-4.05 (m, 1 H), 4.62 (dd, J=9.5, 4.0 Hz, 1 H), 5.04 (s, 2 H),6.60-7.05 (m, 6 H), 7.05 (d, J=8.6 Hz, 2 H), 7.25-7.45 (m, 5 H); MS (ES)m/z: 562.0 (MH⁺, 100%); 1123.5 (2MH⁺, 5%). HRMS Calcd. for C₃₁H₃₆N₃O₅S(M⁺): 562.2375. Found: 562.2392.

EXAMPLE 755-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione

[0429] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (whichwas obtained in Example 36) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 73 as apale yellowish solid; mp>240° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.45-1.60 (m, 2 H), 2.00-2.15 (m, 2 H), 2.86 (brt, J=9.0 Hz, 2 H),2.90-3.60 (m, 3 H), 3.91 (brd, J=9.4 Hz, 1 H), 3.93-4.10 (m, 3 H), 5.40(brs, 1 H), 6.59 (d, J=6.0 Hz, 1 H), 6.63 (d, J=6.0 Hz, 1 H), 6.86 (t,J=6.0 Hz, 1 H), 7.02 (d, J=6.6 Hz, 2 H), 7.36 (s, 1 H), 7.40 (d, J=6.6Hz, 2 H), 11.60 (s, 1 H), 11.70 (brs, 1 H); MS (ES) m/z: 509.9 (MH⁺);HRMS Calcd. for C₂₅H₂₈N₅O₅S (MH⁺): 510.1811. Found: 510.1861.

EXAMPLE 765-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione

[0430] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (whichwas obtained in Example 36) and4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example5) according to the procedure of Example 73 as a pale yellowish solid;mp>208° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.60 (m, 2 H),1.90-2.05 (m, 2 H), 2.70-3.50 (m, 5 H), 3.80-4.10 (m, 5 H), 6.90 (d,J=6.7 Hz, 2 H), 6.77 (d, J=6.7 Hz, 2 H), 7.02 (d, J=8.9 Hz, 2 H), 7.35(s, 1 H), 7.39 (d, J=8.9 Hz, 2 H), 8.95 (brs, 1 H); MS (ES) m/z: 469.9(MH⁺); HRMS Calcd. for C₂₄H₂₈N₃O₅S (M⁺): 469.1671. Found: 469.1648.

EXAMPLE 77N-[5-(2-{1-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0431] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (whichwas obtained in Example 36) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example73 as a pale yellowish solid; mp>200° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆), 1.45-1.60 (m, 2 H), 1.90-2.05 (m, 2 H), 2.70-3.50 (m, 5 H),2.94 (s, 3 H), 3.88 (brd, J=9.9 Hz, 2 H), 4.67 (dd, J=7.2, 2.1 Hz, 1 H),6.87 (d, J=6.3 Hz, 1 H), 7.00 (d, J=6.8 Hz, 2 H), 7.06 (dd, J=6.3, 1.5Hz, 1 H), 7.23 (d, J=1.5 Hz, 1 H), 7.33 (s, 1 H), 7.38 (d, J=6.8 Hz, 2H); MS (ES) m/z: 533.0 (MH⁺); HRMS Calcd. for C₂₄H₂₉N₄O₆S₂ (MH⁺):533.1529. Found: 533.1544.

EXAMPLE 78N-[5-(2-{1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0432] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example73 as a pale yellowish solid; mp>150° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.40-1.60 (m, 2 H), 1.90-2.10 (m, 2 H), 2.55-3.60 (m, 7 H),2.93 (s, 3 H), 3.67 (brd, J=12.8 Hz, 2 H), 4.56 (dd, J=9.6, 4.0 Hz, 1H), 4.64 (brd, J=6.5 Hz, 1 H), 6.70-6.95 (m, 3 H), 6.95-7.15 (m, 3 H),7.22 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 535.0 (MH⁺); HRMS Calcd. forC₂₄H₃₁N₄O₆S₂ (MH⁺): 535.1685. Found: 535.1720.

EXAMPLE 795-(4-{4-[2-(3-Chloro-phenyl)-(2R)-2-hydroxyethylamino}-piperidin-1-yl{-benzyl)-thiazolidine-2,4-dione

[0433] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol(which was obtained in Example 1) according to the procedure of Example73 as a pale yellowish solid; mp>195-198° C.; ¹H NMR (300 MHz, DMSO-d₆)δ1.40-1.60 (m, 2 H), 1.85-2.10 (m, 2 H), 2.60-3.50 (m, 7 H), 3.65 (brd,J=12.5 Hz, 2 H), 4.63 (dd, J=9.5, 4.1 Hz, 1 H), 4.74 (dd, J=8.8, 3.1 Hz,1 H), 6.86 (d, J=8.7 Hz, 2 H), 7.05 (d, J=8.7 Hz, 2 H), 7.20-7.50 (m, 4H); MS (ES) m/z: 460.0 (MH⁺); HRMS Calcd. for C₂₃H₂₆ClN₃O₃S (M⁺):459.1383. Found: 459.1376.

EXAMPLE 805-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0434] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 73 as apale yellowish solid; mp 173-175° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.45-1.60 (m, 2 H), 1.90-2.15 (m, 2 H), 2.10-2.95 (m, 5 H),3.03 (brd, J=10.5 Hz, 1 H), 3.26 (dd, J=14.1, 3.8 Hz, 1 H), 3.68 (brd,J=12.4 Hz, 2 H), 3.95-4.05 (m, 3 H), 4.51 (dd, J=10.0, 4.0 Hz, 1 H),6.58 (d, J=7.8 Hz, 1 H), 6.63 (d, J=8.1 Hz, 1 H), 6.75-6.95 (m, 3 H),7.05 (d, J=8.7 Hz, 2 H), 11.60 (s, 1 H), 11.85 (brs, 1 H); MS (ES) m/z:512.0 (MH⁺); HRMS Calcd. for C₂₅H₃₀N₅O₅S (MH⁺): 512.1968. Found:512.1982.

[0435] The free base from above was dissolved in 20 mL of concentratedhydrochloric acid and stirred for 1 hour. The solvent was removed andthe residue was dissolved in methanol. Upon addition of diethyl etherthe solid which was formed was collected to give5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dionedihydrochloride salt as a pale yellowish solid; ¹H NMR (300 MHz,DMSO-d₆) 1.80-2.10 (m, 2 H), 2.10-2.30 (m, 2 H), 2.90-4.30 (m, 12 H),4.90 (dd, J=9.0, 3.0 Hz, 1 H), 6.60 (d, J=6.0 Hz, 1 H), 6.64 (d, J=6.0Hz, 1 H), 6.88 (t, J=6.0 Hz, 1 H), 7.10-7.40 (m, 4 H), 8.90 (brs, 1 H),9.21 (brs, 1 H), 10.62 (s, 1 H), 10.75 (s, 1 H), 12.04 (s, 1 H); MS (ES)m/z: 512.0 (M−2HCl+H)⁺; HRMS Calcd. for C₂₅H₃₀N₅O₅S (M−2 HCl+H)⁺:512.1968. Found: 512.1964.

EXAMPLE 815-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0436] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) and 4-[(2S)-3-amino-2-hydroxy-propoxyl-phenol(which was obtained in Example 5) according to the procedure of Example73 as a pale yellowish solid; mp>160° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.35-1.60 (m, 2 H), 1.85-2.05 (m, 2 H), 2.60-3.50 (m, 7 H),3.67 (brd, J=12.1 Hz, 2 H), 3.75-3.95 (m, 3 H), 4.57 (dd, J=9.6, 3.8 Hz,1 H), 6.66 (d, J=8.9 Hz, 2 H), 6.77 (d, J=8.9 Hz, 2 H), 6.85 (d, J=8.6Hz, 2 H), 7.03 (d, J=8.6 Hz, 2 H), 8.92(brs, 1 H); MS (ES) m/z: 472.0(MH⁺); HRMS Calcd. for C₂₄H₃₀N₃O₅S (MH⁺): 472.1906. Found 472.1898.

EXAMPLE 825-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-thioxo-thiazolidin-4-one

[0437] The title compound was prepared from1-[4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Example 34) and4-[(2S)-3-amino-2-hydroxy-propoxy]-phenol (which was obtained in Example5) according to the procedure of Example 73 as a pale yellowish solid;MS (ES) m/z: 485.9 (MH⁺).

EXAMPLE 835-{4-[4-((2S)-2-Hydroxy-3-phenoxy-propylamino)-piperidin-1-yl[-benzylidene}-thiazolidine-2,4-dione

[0438] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (whichwas obtained in Example 36) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Example 3) according to the procedure of Example73 as a pale yellowish solid; mp 208-210° C.; MS (ES) m/z: 454.0 (MH⁺);HRMS Calcd. for C₂₄H₂₇N₃O₄S (M⁺): 453.1723. Found: 453.1710.

EXAMPLE 84N-[5-((2R)-2-{1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl}-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0439] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example73 as a pale yellowish solid; mp>180° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.40-1.65 (m, 2 H), 1.90-2.10 (m, 2 H), 2.55-3.60 (m, 7 H),2.94 (s, 3 H), 3.61 (brd, J=9.6 Hz, 2 H), 4.61 (dd, J=9.7, 4.0 Hz, 1 H),4.69 (dd, J=9.1, 2.7 Hz, 1 H), 6.70-6.90 (m, 3 H), 7.00-7.15 (m, 3 H),7.23 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 535.0 (MH⁺); HRMS Calcd. forC₂₄H₃₁N₄O₆S₂ (MH⁺): 535.1685. Found: 535.1692.

[0440] The free base (0.15 g) prepared above was dissolved in 30 mL ofMeOH/CH₂Cl₂ (1/4) and treated with hydrogen chloride gas for 10 minutes.Diethyl ether was then added and the solid which was formed wascollected to giveN-[5-((2R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamidedihydrochloride salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.80-2.10 (m, 2 H), 2.15-2.30 (m, 2 H), 2.95-4.00 (m, 10 H), 2.95 (s, 3H), 4.89 (dd, J=6.9, 3.0 Hz, 1 H), 6.94 (d, J=6.0 Hz, 1 H), 7.10 (dd,J=6.0, 3.0 Hz, 1 H), 7.10-7.30 (m, 5 H), 8.79 (s, 1 H), 8.85 (brs, 1 H),9.32 (brs, 1 H), 10.02 (brs, 1 H), 12.05 (s, 1 H); MS (ES) m/z: 535.0(M−2HCl+H)⁺; HRMS Calcd. for C₂₄H₃₁N₄O₆S₂ (M−2HCl+H)⁺: 535.1685. Found:535.1715.

EXAMPLE 85N-[5-(2-{1-[4-(2,5-Dioxo-imidazolidin-4-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0441] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-imidazolidine-2,4-dione(whichwas obtained in Example 42) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example73 as a pale yellowish solid; mp>201° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-2.90 (m, 5 H),2.92 (s, 3 H), 3.70-3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.2 Hz, 1 H), 6.33(s, 1 H), 6.81 (d, J=8.1 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.02 (dd,J=8.1, 1.8 Hz, 1 H), 7.18 (d, J=61.8 Hz, 1 H), 7.47 (d, J=8.7 Hz, 2 H);MS (ES) m/z: 516.1 (MH⁺); HRMS Calcd. for C₂₄H₃₀N₅O₆S (MH⁺): 516.1917.Found: 516.1922.

EXAMPLE 865-(4-{4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-imidazolidine-2,4-dione-piperidin-1-yl}-benzyl)imidazolidine-2,4-dione

[0442] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-imidazolidine-2,4-dione (which wasobtained in Example 44) and(S)-4-[2-hydroxy-3aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 73 as apale yellowish solid; mp>132° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.85 (m, 8 H), 3.50-3.65(m, 2 H), 3.75-4.05 (m, 3 H), 4.22 (t, J=4.6 Hz, 1 H), 6.57 (d, J=7.5Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.80-6.90 (m, 3 H), 6.99 (d, J=8.4Hz, 2 H), 7.87 (s, 1 H), 10.50 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z:495.1 (MH⁺); HRMS Calcd. for C₂₅H₃₁N₆O₅ (M⁺): 495.2356. Found: 495.2368.

EXAMPLE 87N-[5-(2-{1-[4-(2,5-Dioxo-imidazolidin-4-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide

[0443] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-imidazolidine-2,4-dione (which wasobtained in Example 44) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example73 as a pale yellowish solid; mp>105° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.80-2.00 (m, 2 H), 2.50-2.75 (m, 5 H),2.86 (d, J=4.8 Hz, 2 H), 2.93 (s, 3 H), 3.50-3.65 (m, 2 H), 4.24 (t,J=4.8 Hz, 1 H), 4.51 (dd, J=8.2, 4.0 Hz, 1 H), 6.81 (d, J=6.3 Hz, 1 H),6.84 (d, J=5.7 Hz, 2 H), 7.18 (d, J=1.8 Hz, 1 H), 7.85 (brs, 1 H); MS(ES) m/z: 518.0 (MH⁺); HRMS Calcd. for C₂₄H₃₂N₅O₆S (MH⁺): 518.2073.Found: 518.2056.

EXAMPLE 88N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide

[0444] the title compound was prepared from1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Example 43) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example73 as a pale yellowish solid; mp>210° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.80-2.00 (m, 2 H), 2.50-3.00 (m, 5 H),2.92 (s, 3 H), 3.70-3.90 (m, 2 H), 4.47 (dd, J=7.9, 4.4 Hz, 1 H), 6.81(d,J=8.3 Hz, 1 H), 6.90-7.10 (m, 3 H), 7.18 (d, J=2.0 Hz, 2 H), 7.39 (d,J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 532.0 (MH⁺); HRMS Calcd. forC₂₄H₃₀N₅O₅S₂ (MH⁺): 532.1688. Found: 532.1672.

EXAMPLE 894-((2S)-2-Hydroxy-3-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one

[0445] The title compound: was prepared from1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one(which was obtained in Example 45) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 73 as apale yellowish solid; mp>155° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.90 (m, 6 H), 3.24 (dd,J=14.1, 4.0 Hz; 1 H), 3.50-3.75 (m, 2 H), 3.80-4.05 (m, 3 H), 4.50 (dd,J=9.8, 4.0 Hz, 1 H), 4.88 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d,J=8.1 Hz, 1 H), 6.80-6.90 (m, 3 H), 7.04 (d, J=8.7 Hz, 2 H), 8.73 (brs,1 H); MS (ES) m/z: 256.3 ((M+2H)²⁺, 100%), 511.2 (MH⁺, 10%); HRMS Calcd.for C₂₅H₃₁N₆O₄S (MH⁺): 511.2128. Found: 511.2122.

EXAMPLE 90N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide

[0446] The title compound was prepared from1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-one(which was obtained in Example 45) andN-[5-2-amino-1hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (whichwas obtained in Example 9) according to the procedure of Example 73 as apale yellowish solid; mp>90° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.80-2.00 (m, 2 H), 2.50-2.80 (m, 6 H), 2.93 (s, 3H), 3.25 (dd, J=14.2, 3.9 Hz, 1 H), 3.45-3.60 (m, 2 H), 4.40-4.55 (m, 2H), 6.81 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.96 (dd, J=8.3,2.0 Hz, 1 H), 7.04 (d, J=8.6 Hz, 2 H), 7.16 (d, J=2.0 Hz, 1 H); MS (ES)m/z: 267.7 ((M+2H)²⁺100%), 534.3 (MH⁺, 45%), 1067.0 (2MH⁺, 2%); HRMSCalcd. for C₂₄H₃₂N₅O₅S₂ (MH⁺): 534.1845. Found: 534.1850.

EXAMPLE 915-(4-{4-[(2S)-2-Hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0447] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) and(S)-5-(3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one)(whichwas obtained in Example 12) according to the procedure of Example 73 asa pale yellowish solid; mp>140° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.40-1.55 (m, 2 H), 1.85-2.00 (m, 2 H), 2.40 (t, J=8.0 Hz, 2H), 2.60-3.00 (m, 8 H), 3.25 (dd, J=15.9, 3.9 Hz, 1 H), 3.50-3.70 (m, 2H), 3.80-4.00 (m, 3 H), 4.50 (dd, J=9.7, 3.9 Hz, 1 H), 6.34 (d, J=8.9Hz, 1 H), 6.61 (d, J=8.9 Hz, 1 H), 6.85 (d, J=8.6 Hz, 2 H), 7.05 (d,J=8.6 Hz, 2 H), 8.76 (s, 1 H), 9.24 (brs, 1 H); MS (ES) m/z: 541.1(MH⁺); HRMS Calcd. for C₂₇H₃₃N₄N₄O₆S (MH⁺): 541.2121. Found: 541.2148.

EXAMPLE 92N-[5-((2S)-3-{1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide

[0448] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 14) according to the procedure of Example73 as a grey solid; mp>70° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.45-1.55 (m, 2 H), 1.85-2.00 (m, 2 H), 2.60-2.90 (m, 6 H), 2.94 (s, 3H), 3.23 (dd, J=14.0, 3.8 Hz, 1 H), 3.60-4.00 (m, 5 H), 4.49 (dd, J=8.8,3.9 Hz, 1 H), 6.64 (dd, J=8.8, 3.0 Hz, 1 H), 6.75-6.90 (m, 4 H), 7.04(d, J=8.6 Hz, 2 H); MS (ES) m/z: 564.8 (MH⁺, 100%); HRMS Calcd. forC₂₅H₃₃N₄O₇S₂ (MH⁺): 565.1791. Found: 565.1783.

EXAMPLE 93N-[5-((2S)-3-{1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide

[0449] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) andN-[5-(3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide(which was obtained in Example 21) according to the procedure of Example73 as an off-white solid; mp>120° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.30-1.55 (m, 2 H), 1.80-2.00(m, 2 H), 2.50-4.00(m, 12 H),4.55(dd, J=9.6, 4.0 Hz, 1 H), 6.49(dd, J=8.7, 2.9 Hz, 1 H), 6.61(d,J=8.7 Hz, 1 H), 6.77(d, J=2.9 Hz, 1 H), 6.86(d, J=8.7 Hz, 2 H), 7.05(d,J=8.7 Hz, 2 H), 7.40-7.60(m, 3 H), 7.70-7.80(m, 2 H); MS (ES) m/z: 627.0(MH⁺, 100%); HRMS Calcd. for C₃₀H₃₅N₄O₇S₂ (MH⁺): 627.1941. Found:627.1954.

EXAMPLE 94 (R)-Propane-2-sulfonic acid[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide

[0450] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) and propane-2-sulfonic acid[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide(which wasobtained in Example 27) according to the procedure of Example 73 as awhite solid; mp>175° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.25(d,J=6.8 Hz, 6 H), 1.30-1.55 (m, 2 H), 1.80-2.00(m, 2 H), 2.60-3.70(m, 9H), 4.47(dd, J=9.7, 3.9 Hz, 1 H), 4.58(dd, J=8.7, 3.4 Hz, 1 H),6.75-6.90(m, 3 H), 6.90-7.10(m, 3 H), 7.26(d, J=2.0 Hz, 1 H); MS (ES)m/z: 563.0 (MH⁺, 100%); HRMS Calcd. for C₂₆H₃₅N₄O₆S₂ (MH⁺): 563.1992.Found: 563.1985.

EXAMPLE 95N-[2-Chloro-5-((1R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-phenyl]-methanesulfonamide

[0451] To a stirred mixture of copper(II) sulfate pentahydrate (0.042 g,0.17 mmol) in N,N-dimethylformamide (15 mL) was added sodium borohydride(0.037 g, 1 mmol). To the resulting suspension was addedN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide(whichwas obtain in Example 25)(0.11 g, 0.38 mmol). After stirring for 20minutes more copper(II) sulfate pentahydrate (0.042 g, 0.17 mmol) andsodium triacetoxyborohydride (0.064 g, 0.3 mmol) was added. The reactionmixture was stirred for 2.5 hours and then5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38)(0.116 mg, 0.38 mmol), sodiumtriacetoxyborohydride (0.212 g, 1.0 mmol), and acetic acid (0.2 mL) wereadded. After stirring for 1.5 hours aqueous sodium bicarbonate solutionwas added and the resulting solid was collected. The product waspurified by flash silica gel chromatography eluting with methylenechloride and methanol to give the title compound as a pale grey solid;mp>105° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.30-1.50(m, 2 H),1.80-2.00(m, 2 H), 2.60-3.60(m, 9 H), 3.00(s, 3 H), 4.40-4.55(m, 1 H),4.65-4.75(m, 1 H), 6.84(d, J=8.4 Hz, 2 H), 7.04(d, J=8.4 Hz, 1 H),7.20(d, J=8.1 Hz, 1 H), 7.40-7.50(m, 2 H); MS (ES) m/z: 553.2 (MH⁺,100%); HRMS Calcd. for C₂₄H₃₀ClN₄O₅S₂ (MH⁺): 553.1440. Found: 553.1336.

EXAMPLE 96N-(5-{(1R)-2-[(1-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidin-4-yl)amino]-1-hydroxethyl}-2-hydroxyphenyl)benzenesulfonamide

[0452] The title compound was prepared from5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which wasobtained in Example 38) andN-[5-((R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-phenylsulfonamide(which was obtained in Example 32) according to the procedure of Example73 as a white solid; mp>150° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.39(m, 4 H), 1.85(m, 4 H), 2.64 (m, 2 H), 2.89(s, 3 H), 4.48(m, 1 H),6.77(d, J=6 Hz, 1 H), 6.86(m, 2 H), 7.02(m, 2 H), 7.48(m, 2 H), 7.72(d,J=6 Hz, 1H); MS (ES) m/z: 597.0 (MH⁺, 100%); HRMS Calcd. forC₂₉H₃₂N₄O₆S₂(MH⁺): 597.1836. Found: 597.1827.

EXAMPLE 97N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide

[0453] The title compound was prepared from1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidin-4-one (which was obtained inExample 47) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example73 as a white solid; mp>175° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.40-1.65 (m, 2 H), 1.90-2.10 (m, 2 H), 2.70-3.10 (m, 5 H), 2.95 (s, 3H), 3.70-3.85 (m, 2 H), 4.69 (dd, J=9.3, 3.0 Hz, 1 H), 6.89 (d, J=8.3Hz, 1 H), 6.97 (d, J=8.9 Hz, 2 H), 7.06 (dd, J=8.3, 2.0 Hz, 1 H), 7.24(d, J=2.0 Hz, 1 H), 7.80 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 474.1 (MH⁺);HRMS Calcd. for C₂₁H₂₈N₇O₄S (MH⁺): 474.1918. Found: 474.1912.

EXAMPLE 98 Ethyl[5-(4-{4-((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]acetate

[0454] The title compound was prepared fromethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-1H-tetraazol-1-yl}acetate(which was obtained in Example 48) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedures ofExample 34 and Example 73 as a white solid; mp>140° C. (decomposed); ¹HNMR (300 MHz, DMSO-d₆) δ1.17 (t, J=7.1 Hz, 3 H), 1.20-1.40 (m, 2 H),1.80-1.95 (m, 2 H), 2.50-3.50 (m, 5 H), 2.89 (s, 3 H), 3.70-3.90 (m, 2H), 4.11 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=7.8, 4.4 Hz, 1 H), 5.60 (brs, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.96 (dd, J=8.2, 2.0 Hz, 1 H), 7.07 (d,J=8.9 Hz, 2 H), 7.16 (d, J=2.0 Hz, 1 H), 7.56 (d, J=8.9 Hz, 2 H); MS(ES) m/z: 560.2 (MH⁺); HRMS Calcd. for C₂₁H₂₈N₇O₄S (MH⁺): 560.2286.Found: 560.2282.

EXAMPLE 99[5-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino[phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]aceticacid

[0455] The title compound was prepared from ethyl[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]acetate(which was obtained in Example 98) by NaOH hydrolysis as an off-whitesolid; mp>210° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.30-1.50 (m,2 H), 1.80-2.00 (m, 2 H), 2.60-3.50 (m, 5 H), 2.92 (s, 3 H), 3.70-3.85(m, 2 H), 4.50-4.60 (m, 1 H), 4.70-4.80 (m, 2 H), 6.84 (d, J=8.2 Hz, 1H), 6.95-7.05 (m, 3 H), 7.20 (d, J=1.6 Hz, 1 H), 7.66 (d, J=8.7 Hz, 2H); MS (ES) m/z: 530.2 (M−H)⁻; HRMS Calcd. for C₂₁H₂₈N₇O₄S (M−H)⁻:530.1827. Found: 530.1827.

EXAMPLE 100[5-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2H-tetraazol-2-yl]aceticacid

[0456] The title compound was prepared from ethyl{5-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2H-tetraazol-2-yl}acetate(which was obtained in Example 48) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedures ofExample 98 and Example 99 as a white solid; mp>240° C. (decomposed); ¹HNMR (300 MHz, DMSO-d₆) δ1.45-1.65 (m, 2 H), 1.90-2.10 (m, 2 H),2.50-3.10 (m, 5 H), 2.95 (s, 3 H), 3.65-3.85 (m, 2 H), 4.89 (brd, J=8.3Hz, 1 H), 5.08 (d, J=15.9 Hz, 1 H), 5.15 (d, J=15.9 Hz, 1 H), 6.88 (d,J=8.3 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2 H), 7.09 (dd, J=8.3, 2.0 Hz, 1 H),7.26 (d, J=2.0 Hz, 1 H), 7.87 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 532.1(MH⁺); HRMS Calcd. for C₂₁H₃₀N₇O₄S (MH⁺): 532.1973. Found: 532.1965.

EXAMPLE 101 Trifluoromethylthioacetamide

[0457] A mixture of trifluoroacetamide (45.2 g, 0.4 mol), Lawesson'sReagent(2,4-bis(4-methoxyphenyl)-1,3-thia-2,4-diphosphetane-2,4-disulfide)(81.7 g, 0.202 mol) and benzane (600 mL) was refluxed for 20 hours. Thevolatiles were removed in vacuo and the residue was purified by silicagel filtration (hexanes/dichloromethane 1/1) to give light yellow solid(24 g, 47% yield); MS (ES) m/z: 130 (MH⁺); ¹H NMR (300 MHz, DMSO-d₆)δ6.90 (d, 1H), 7.60 (d, 1H).

EXAMPLE 102 2-Bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanone

[0458] A solution of trifluoromethylthioacetamide (which was obtained inExample 101)(14 g, 0.11 mol) in acetonitrile (200 mL) was added dropwiseinto a boiling solution of 1,4-dibromo-2,3-butanedione (26.4 g, 0.11mol) in acetonitrile (200 mL) over a period of 2.5 hours. The volatileswere removed in vacuo and the residue was purified by flashchromatography (hexanes/toluene 6/4) to give a light pink colored solid(7.0 g, 24% yield); mp 36-37° C.; MS (ES) m/z: 273 (M−H)⁻; ¹H NMR (400MHz, CDCl₃) δ4.64 (s, 2H), 8.50 (s, 1H).

EXAMPLE 103(1S)-2-Bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanol

[0459] Borane (in THF, 1M, 10.35 mL, 10.5 mmol) was added dropwise intoa mixture of (R)-2-methyl-CBS-oxazaborolidine monohydrate (0.38 g, 1.31)mmol and tetrahydrofuran (15 mL) under a nitrogen atmosphare at ambienttemperature. The mixture was stirred for 10 minutes and then2-bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanone (which wasobtained in Example 102)(3.6 g, 13.13 mmol) in tetrahydrofuran (20 mL)was added dropwise over 10 minutes. The new mixture was stirred at roomtemperature for 4 hours. The reaction mixture was cooled to 0° C. andquenched with a hydrogen chloride/ethyl ether solution (1M, 1.0 mL).After stirring at 0° C. for 30 minutes, H₂O (20 mL) was added dropwiseand the mixture was extracted with ethyl ether. The organic layer waswashed with aqueous ammonium chloride and dried over MgSO₄. Evaporationand purification by flash chromatography(hexanes/dichloromethane/ethanol 1/1/0.01) gave a clear oil (2,4 g, 66%yield); MS (ES) m/z: 334/336 (M+acetic acid−H)⁻; ¹H NMR (400 MHz, CDCl₃)δ2.94 (m, 1H), 3.74 (m, 1H), 3.94 (m, 1H), 5.16 (m, 1H), 7.62 (s, 1H).

EXAMPLE 104 4-[(2S)-Oxiran-2-yl]-2-trifluoromethyl-1,3-thiazole

[0460] Aqueous sodium hydroxide (5N, 11 mL) was added to a solution of(1S)-2-bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanol (which wasobtained in Example 103)(1.52 g, 5.5 mmol) in tetrahydrofuran (6 mL).The mixture was stirred at room temperature for 18 hours. The reactionmixture was diluted with H₂O (30 mL) and extracted with dichloromethane.The organic extracts were washed with H₂O and brine, and dried overMgSO₄. Evaporation and purification by flash chromatography(hexanes/dichloromethane 6/4) gave a clear oil (1.33 g, 74% yield); MS(ES) m/z: 196 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ3.09 (m, 1H), 3.19(m, 1H),4.11(m, 1H), 7.48 (s, 1H).

EXAMPLE 105 (1S)-(2-Amino-1-[2-trifluoromethyl-1,3-thiazole-4-yl]ethanol

[0461] Ammonia (20 g) was bubbled over 1 hour into a cold (−40° C.)pressure vessel containing4-[(2S)-oxiran-2-yl]-2-trifluoromethyl-1,3-thiazole(which was obtainedin Example 104)(0.13 g, 6.8 mmol) and methyl alcohol (40 mL). Thereaction vessel was sealed, warmed up to room temperature and stirredfor 48 hours. The methyl alcohol was removed in vacuo and the productwas purified by flash chromatography (chloroform/methylalcohol/triethylamine 8/2/0.01) to give a white solid (0.65 g, 45%yield); MS (ES) m/z: 213 (MH⁺); ¹H NMR (400 MHz, CDCl₃) δ3.05 (m, 1H),3.21(m, 1H), 4.85(m, 1H), 7.55 (s, 1H).

EXAMPLE 1065-{4-[4-({(2S)-2-Hydroxy-2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethyl}amino)piperidine-1-yl]benzyl}-1,3-thiazolidine-2,4-dione

[0462] A mixture of(1S)-(2-amino-1-[2-trifluoromethyl]-1,3-thiazole-4-yl]ethanol (which wasobtained in Example 105)(0.34 g, 1.59 mmol) and5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38)(0.48 g, 1.59 mmol), sodium triacetoxyborohydride(0.67 g, 3.18 mmol), and acetic acid (0.33 mL) in N,N-dimethylformamide(15 mL) was stirred at room temperature for 18 hours, poured intoaqueous ammonium chloride and extracted with ethyl acetate. The organicextracts were washed with brine and dried over MgSO₄. Evaporation andpurification by flash chromatography (chloroform/methyl alcohol 9.5/5)gave a yellow solid (0.1 g, 13% yield); mp 108-113° C.; MS (ES) m/z: 501(MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ1.44 (m, 2H), 1.93 (s, 2H), 3.23-2.66(m, 7H), 3.62 (d, 2H) 4.68 (m, 1H), 4.94 (m, 1H), 6.86 (d, 2H), 7.5 (d,2H), 8.3 (s, 1H); Anal. Calcd. for C₂₁H₂₃F₃N₄O₃S₂: C, 50.39; H, 4.63; N,11.19. Found: C, 50.16; H, 5.16; N, 9.93.

EXAMPLE 107 (1S)-2-Bromo-1-[3-(3,4-dichlorophenyl)isoxazol-5-ylmethanol

[0463] The title compound was prepared from5-(bromoacetyl)-3-(3,4-dichlorophenylisooxazole), 1M BH₃/THF, and(R)-2-methyl-CBS-oxazaborolidine monohydrate in substantially the samemanner as described in Example 103 and was obtained as a white solid(4.5 g, 89% yield), mp 103-104° C.; MS m/z: 335 (M⁺); ¹H NMR (400 MHz,DMSO-d₆) δ3.76 (m, 2H), 5.05 (m, 1H), 6.50 (d, 1H), 7.17 (s, 1H), 7.90(d, 1H), 7.92 (d, 1H), 8.34 (s, 1H).

EXAMPLE 108 3-(3,4-Dichlorophenyl)-5-[(2S)-oxiran-2-yl]isoxazole

[0464] The title compound was prepared from(1S)-2-bromo-1-[3-(3,4-dichlorophenyl)isoxazol-5-ylmethanol (which wasobtained in Example 107), in aqueous sodium hydroxide (5N) insubstantially the same manner as described in Example 104 and wasobtained as a white solid (1.6 g, 84% yield); mp 74° C.; MS (ES) m/z:256 (MH⁺): ¹H NMR (400 MHz, CDCl₃) δ3.25 (m, 2H), 4.04 (d, 1H), 6.54 (s,1H), 7.54 (d, 1H), 7.62 (d, 1H), 7.89 (s, 1H).

EXAMPLE 109 (1S)-2-Amino-1-[3-(3,4-dichlorophenyl)isoxazol-5-yl]ethanol

[0465] The title compound was prepared from3-(3,4-dichlorophenyl)-5-[(2S)-oxiran-2-yl]isoxazole (which was obtainedin Example 108), in methyl alcohol and ammonia in substantially the samemanner as described in Example 105, and was obtained as a white solid(0.43 g, 80% yield), mp 105° C.; MS (ES) m/z: 273 (MH⁺); ¹H NMR (400MHz, CDCl₃) δ3.18 (m, 2H), 4.83 (m, 1H), 6.56 (s, 1H),7.54 (d, 1H), 7.62(d, 1H), 7.90 (s, 1).

EXAMPLE 1105-{4-[4-({(2S)-2-[3-(3,4-Dichlorophenyl)isoxazol-5-yl]-2-hydroxyethyl}-amino)piperidine-1-yl}benzyl}-1,3-thiazole-2,4-dione

[0466] The title compound was prepared from(1S)-2-amino-1-[3-(3,4-dichloro-phenyl)isoxazol-5-yl]ethanol (which wasobtained in Example 109) and5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38) in substantially the same manner, as describedin Example 106 and was obtained as a white solid (0.22 g, 48% yield), mp110° C.; MS (ES) m/z: 561 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ1.38 (m,2H), 1.89 (m, 2H), 3.32-2.67 (m, 7H), 3.60 (m, 2H), 4.74 (m. 1H), 4.85(m, 1H), 6.85 (d, 1H), 7.02 (d, 1H), 7.11 (s, 1H), 7.79 (d, 1H), 7.86(d, 1H), 8.13 (s, 1H).

EXAMPLE 111 N-[4-(2-Bromoacetyl)phenyl]methanesulfonamide

[0467] A solution of bromine (0.73 mL, 14.06 mmol) in methylene chloride(5 mL) was added at room temperature over 10 minutes to a mixture ofN-[4-(2-bromoacetyl)phenyl]-methanesulfonamide (Uloth, R. H. et al. J.Med. Chem., 1966, 88-97) (2.41 g, 8.25 mmol),(R)-2-methyl-CBS-oxazaborolidine monohydrate (3 g, 14.06 mmol),benzoylperoxide (0.05 g), and methylene chloride (40 mL). The newmixture was stirred for 60 hours. The precipitate was collected, washedwith ethyl ether and crystallized from ethanol to give an off-whitesolid (2.5 g, 60% yield); MS (ES) m/z: 291 (M)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ3.14 (s, 3H), 4.82 (s, 2H), 7.25 (d, 2H), 7.95 (d, 2H),10.21(s, 1H); Anal. Calcd. for: C₉H₁₀BrNO₃S: C, 37.00, H, 3.45, N, 4.79.Found: C, 36.26, H, 3.19, N, 4.67.

EXAMPLE 112 N-{4-[(1R)-2-Bromo-1-hydroxyethyl]phenyl}methanesulfonamide

[0468] The title compound was prepared fromN-[4-(2-bromoacetyl)phenyl]methanesulfonamide (0.23 g, 0.82 mmol)(whichwas obtained in Example 111), and 1M BH₃/THF solution (10.35 mL, 10.5mmol) in substantially the same manner, as described in Example 103 andwas obtained as a white solid (1.75 g, 72% yield); MS (ES) m/z: 293(M)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.14 (d, 2H), 2.95 (s, 3H), 3.53 (m,1H), 3.55 (m, 1H), 4.73 (m, 1H), 5.75 (d, 1H), 7.14 (d, 2H), 9.74 (s,1H).

EXAMPLE 113 N-{4-[(1R)-Azido-1-hydroxyethyl]phenyl}methanesulfonamide

[0469] A mixture ofN-{4-[(1S)-2-bromo-1-hydroxyethyl]phenyl}methanesulfonamide (which wasobtained in Example 112)(1.73 g, 5.9 mmol), sodium iodide (0.88 g, 5.9mmol), sodium azide (1.53 g, 23.6 mmol), and methyl sulfoxide (15 mL)was stirred at ambient temperature for 7 days, poured into water andextracted with ethyl acetate. The organic extracts were washed withwater, and dried over MgSO₄. Evaporation and purification by flashchromatography (hexanes/chloroform/isopropylalcohol,5/4.5/0.5) gave anoff-white solid (0.56 g, 70% yield); MS (ES) m/z: 256 (M)⁺; ¹H NMR (400MHz, DMSO-d₆) δ2.94 (s, 3H), 3.30 (m, 2H), 4.74 (m, 1H), 5.75 (d, 1H),7.17 (d, 2H), 7.32 (d, 2H), 9.67(s, 1H).

EXAMPLE 114 N-{4-[(1R)-2-Amino-1-hydroxyethyl]phenyl}methanesulfonamide

[0470] A mixture ofN-{4-[(1S)-azido-1-hydroxyethyl]phenyl}methanesulfonamide (which wasobtained in Example 113)(0.55 g, 2.146 mmol), 10% Pd/C (0.03 g) andmethanol (30 mL) was hydrogenated on a Parr shaker at 50 psi for 3hours. The catalyst was removed by filtration through celite. Thefiltrate was concentrated under vacuo to give an off-white solid (0.48g, 97% yield); MS (ES) m/z: 231 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ2.57(m, 2H), 2.94 (s, 3H), 3.4-4.2 (br, 2H), 4.38 (m, 1H), 4.6-5.8 (br, 2H),7.23 (d, 2H), 7.26 (d, 2H).

EXAMPLE 115N-(4-{(1R)-2-[(1-{4-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidine-4-yl)amino]-1-hydroxyethyl)}phenyl)methanesulfonamide

[0471] The title compound was prepared fromN-{4-[(1R)-2-amino-1-hydroxyethyl]phenyl}methanesulfonamide(which wasobtained in Example 114) and5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38) in substantially the same manner, as describedin Example 106 and was obtained as a white solid(0.33 g, 50% yield); mp138-145° C.; MS (ES) m/z: 519 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ1.49 (m,2H), 1.97 (m, 2H), 2.65 (t, 2H), 2.88-2.95 (br, 5H), 3.20-3.45 (br, 3H),3.63 (d. 2H), 4.68 (m, 1H), 4.70 (m, 1H), 6.85 (d, 2H), 7.02 (d, 2H),7.18 (d, 2H), 7.32 (d, 2H), 8.01-9.21 (br, 3).

EXAMPLE 116 Dibromoformaldoxime

[0472] A mixture of glyoxylic acid monohydrate (96.63 g, 1.05 mol),hydroxylamine hydrochloride (73.7 g, 1.06 mol) and water was stirred atambient temperature for 18 hours. Sodium bicarbonate (176.4 g, 2.1 mol)was carefully added over 30 minutes followed by methylene chloride (600mL). The new mixture was cooled to 5° C. and a solution of bromine (75mL, 2.9 mol) in methylene chloride (350 mL) was added at such a ratethat the temperature did not rise above 5° C. Upon completion of theaddition of bromine the mixture was further stirred at 5° C. and theorganic layer was separated. The aqueous layer was extracted withmethylene chloride. The combined organic extracts were dried over MgSO₄.Evaporation and purification by recrystallization from hexanes gave awhite solid (32.5 g, 15% yield); ¹H NMR (400 MHz, DMSO-d₆) δ11.73 (s,1H).

EXAMPLE 117 3-Bromo-5-acetylisoxazole

[0473] A mixture of dibromoformaldoxime(which was obtained in Example116) (32.5 g, 160.2 mmol), 3-butyn-one (13.41 g, 197 mmol), potassiumcarbonate (11 g, 80.1 mmol), and methylene chloride (300 mL) was stirredat ambient temperature for 20 hours. The slurry was then treated withaqueous hydrochloric acid (2 N, 200 mL) and extracted with methylenechloride. The combined organic extracts were dried over MgSO₄.Evaporation and purification by flash chromatography (ethylacetate/hexanes 5/95) gave a white solid (16.76 g, 56% yield); ¹H NMR(300 MHz, CDCl₃) δ2.62 (s, 3H), 6.97 (s, 1H).

EXAMPLE 118 3-Bromo-5-(bromoacetyl)isoxazole

[0474] A mixture of 3-bromo-5-acetylisoxazole (which was obtained inExample 117)(16.7 g, 87.9 mmol), phenyltrimethylammonium tribromide(33.4g, 88.8 mmol) and tetrahydrofuran (150 mL) was stirred at ambienttemperature for 18 hours, poured into water and extracted with ether.The organic extracts were washed with brine and dried over MgSO₄.Evaporation and purification by distillation gave a light yellow oil(8.9 g, 40% yield); ¹H NMR (300 MHz, CDCl₃) δ4.40. (s, 3H), 7.10 (s,1H).

EXAMPLE 119 (1R)-2-Bromo-1-(3-bromoisoxazole-5-yl)ethanol

[0475] The title compound was prepared from3-bromo-5-(bromoacetyl)isoxazole(which was obtained in Example 118),(R)-2-methyl-CBS-oxaborolidine monohydrate, and 1 M BH₃/THF solution insubstantially the same manner, as described in Example 103 with onechange; the crude product was purified by flash chromatography andreverse phase chromatography to give a colorless oil (1.45 g, 16%yield): ¹H NMR (300 MHz, CDCl₃) δ3.67-3.81(m, 2H), 5.16. (m, 1H), 6.49(s, 1H).

EXAMPLE 120 3-Bromo-5-[(2S)-oxiran-2-yl]isoxazole

[0476] A mixture of (1R)-2-bromo-1-(3-bromoisoxazole-5-yl)ethanol (whichwas obtained in Example 119)(1.44 g, 5.31 mmol), potassium carbonate(1.46 g, 10.62 mmol) and acetone (30 mL) was stirred at ambienttemperature for 48 hours. The reaction mixture was filtered, and thesolvent was removed in vacuo. The residue was purified by flashchromatography (hexanes/chloroform/isopropyl alcohol 8/1.8/0.2) to givea colorless oil (0.774 g, 53% yield); ¹H NMR (300 MHz, CDCl₃) δ3.17 (m,1H), 3.21 (m, 1H), 3.99 (m, 1H), 6.38 (s, 1H).

EXAMPLE 121 (1S)-2-Amino-1-(3-bromoisoxazole-5-yl)ethanol

[0477] The title compound was prepared from3-bromo-5-[(2S)-oxiran-2-yl]isoxazole(which was obtained in Example 120)in substantially the same manner as described in Example 105 and wasobtained as an off-white solid (0.54 g, 90% yield): MS (ES) m/z: 207(MH)⁺; ¹H NMR (400 MHz, CDCl₃) δ1.7(br, 3H), 3.13 (br, 2H), 4.77 (t,1H), 6.35 (s, 1H).

EXAMPLE 1225-[4-(4-{[4-(2S)-2-(3-Bromoisoxazol-5-yl)-2-hydroxyethyl]amino}piperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione

[0478] The title compound was prepared from(1S)-2-amino-1-(3-bromoisoxazole-5-yl)ethanol(which was obtained inExample 121) and5-[4-(4-oxopiperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38) in substantially the same manner, as describedin Example 106 and was obtained as a white solid (0.13 g, 88% yield); mp145-150° C.; MS (ES) m/z: 519 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ1.49 (m,2H), 1.97 (m, 2H), 2.65 (t, 2H), 288-2.95 (br, 5H), 3.20-3.45 (br, 3H),3.63 (d, 2H), 4.68 (m, 1H), 4.70 (m, 1H), 6.85 (d, 2H), 7.02 (d, 2H),7.18 (d, 2H), 7.32 (d, 2H), 8.00-9.20 (br, 3H).

EXAMPLE 123 3-(2-Oxiranylmethoxy)pyridine

[0479] Sodium hydride (60%, 2.16 g, 54.0 mmol) was added portionwiseinto N,N-dimethylformamide (50 mL) with stirring at room temperatureunder a nitrogen atmosphere. A solution of 3-pyridinol (4.5 g, 46.28mmol) in N,N-dimethylformamide (50 mL) was then added dropwise to thissuspension over a period of 0.5 hour. After stirring for 1 hour asolution of (2S)-oxiranylmethyl 3-nitrobenzenesulfonate (10 g, 38.57mmol) in N,N-dimethylformamide (50 mL) was added dropwise into thismixture over a period of 15 minutes. The mixture was then stirred atroom temperature overnight. The reaction was quenched with aqueousammonium chloride to pH 5 and extracted with ethyl acetate. The extractswere washed with water and dried with brine. Evaporation andpurification by flash column chromatography (dichloromethane/methylalcohol 95/5) gave a brown oil (1.44 g, 25% yield); ¹H NMR (400 MHz,DMSO-d₆) δ2.71-2.73 (m, 1 H), 2.81-2.84 (m, 1 H), 3.34-3.38 (m, 1 H),3.87-3.92 (m, 1 H), 4.40-4.43 (m, 1 H), 7.30-7.33 (m, 1 H), 7.39-7.41(m, 1 H), 8.71-8.19 (m, 1 H), 8.31 (s, 1 H); MS (ES) m/z: 152 (MH⁺).

EXAMPLE 124 (2S)-1-Amino-3-(3-pyridinyloxy)-2-propanol

[0480] A solution of 3-(2-oxiranylmethoxy)pyridine (which was obtainedin Example 123)(1.41 g) in 120 mL of saturated ammonium methanol wasstirred at 0° C. for two days. The reaction mixture was concentrated togive a yellow semi-solid (1.56 g, 99.5% yield); ¹H NMR (400 MHz,DMSO-d₆) δ1.60 (brs, 2 H), 2.55-2.59 (m, 1 H), 2.61-2.68 (m, 1 H),3.67-3.72 (m, 1 H), 3.89-3.93 (m, 1 H), 4.00-4.04 (m, 1 H), 4.90 (brs, 1H), 7.29-7.32 (m, 1 H), 7.36-7.38(m, 1H), 8.13-8.14 (d, 1 H), 8.27 (s, 1H); MS (ES) m/z: 138(M⁺); Anal. Calcd. for C₇H₁₀N₂O: C, 57.13; H, 7.19;N, 16.66. Found: C, 57.83; H, 7.17; N, 18.98.

EXAMPLE 1255-(4-{4-[(2S)-2-Hydroxy-3-(pyridin-3-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0481] (2S)-1-Amino-3-(3-pyridinyloxy)-2-propanol (0.21 g, 1.25 mmol)(which was obtained in Example 124) and5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38)(0.413, 1.25 mmol) were mixed inN,N-dimethylformamide (12 mL) and then treated with sodiumtriacetoxyborohydride (0.56 g, 2.5 mmol) and acetic acid (0.26 mL).After stirring, at room temperature under a nitrogen atmosphere for oneday, the mixture was purified by column chromatography(dichloromethane/methyl alcohol 85/5) to give the title compound as ayellow solid (0.25 g, 56% yield); mp; 130-132° C.; ¹H NMR (400 MHz,DMSO-d₆) δ1.20-1.54 (m, 2 H), 1.90-2.02 (m, 2H), 2.67 (t, 2 H),2.78-2.97 (m, 4 H), 3.22-3.26 (m, 1 H), 3.35 (brs, 2 H), 3.64-3.70 (d, 2H), 3.97-4.08 (m, 3 H), 4.60-4.63 (m, 1 H), 6.84-6.86 (m, 2 H),7.03-7.05 (m, 2 H), 730-7.36 (m, 1 H), 7.38-7.40 (m, 1 H), 8.16-8.17 (m,1 H), 8.829-8.30 (m, 1 H); MS (ES) m/z: 457 (MH⁺).

EXAMPLE 126 2-Methyl-5-(2-oxiranylmethoxy)pyridine

[0482] The title compound was prepared from 6-methyl-3-pyridinol and(2S)-oxiranylmethyl 3-nitrobenzenesulfonate in substantiallly the samemanner as described in Example 123. The product was obtained as a brownoil; ¹H NMR (400 MHz, DMSO-d₆) δ2.38 (s, 2.38, 1H), 2.68-2.70 (m, 1 H),2.81-2.84 (m, 1 H), 3.30-3.34 (m, 1 H), 3.83-3.87 (m, 1 H), 4.34-4.38(m, 1 H), 7.15-7.17 (m, 1 H), 7.28-7.31 (m, 1 H), 8.15-8.16 m (m, 1 H);MS (ES) m/z: 165 (M)⁺

EXAMPLE 127 (2S)-1-Amino-3-[(6-methyl-3-pyridinyl)oxy]-2-propanol

[0483] The title compound was prepared from2-methyl-5-(2-oxiranyl-methoxy)pyridine(which was obtained in Example126) in substantially the same manner as described in Example 124. Theproduct was obtained as an oil; ¹H NMR (400 MHz, DMSO-d₆) δ1.65 (brs, 2H), 2.37 (s, 1 H), 2.53-2.58 (m, 1 H), 2.63-2.69 (m, 1 H), 4.60 (brs, 1H), 3.84-3.88 (m, 1 H), 3.95-3.99 (m, 1 H), 7.13-7.15 (m, 1 H),7.25-7.28 (m, 1 H), 8.12-8.13 (m, 1 H), 8.13-8.14 (d, 1 H); MS (ES) m/z:183 (MH⁺).

EXAMPLE 1285-(4-{4-[(2S)-2-Hydroxy-3-(6-methyl-pyridin-3-yloxy)-propylamino]-piperin-1-yl}-benzyl)-thiazolidine-2,4-dione

[0484] The title compound was prepared from(2S)-1-amino-3-[(6-methyl-3-pyridinyl)oxy]-2-propanol (which wasobtained in Example 127) and5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which wasobtained in Example 38) in substantially the same manner, as describedin Example 125. The product was obtained as a yellow solid; mp 87° C.(decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ1.44-1.49 (m, 2 H), 1.93-1.97(m, 2 H), 2.38 (s, 3 H), 2.64-2.70 (m, 2 H), 2.77-2.95 (m, 4 H),3.23-3.27 (m, 1H), 3.35 (brs, 2 H), 3.64-3.67 (m, 2H), 3.93-4.02 (m, 3H), 4.58-4.62 (m, 1 H), 6.84-6.86 (m, 2 H), 7.03-7.05 (m, 2 H),7.15-7.17 (m, 1 H), 7.27-7.30 (m, 1 H), 8.14-8.15 (m, 1 H); MS (ES) m/z:469 (M−H)⁻.

EXAMPLE 129 3-[(2S)-Oxiranyl]pyridine

[0485] A solution of borane-THF (1.0 M solution, 22.8 mL) was addeddropwise into a cold (0° C.) solution of(S)-2-methyl-CBS-oxazaborolidine monohydrate (1.12 g, 3.8 mmol) intetrahydrofuran (20 mL), over a period of 10 minutes. After stirring at0° C. for 10 minutes, the mixture was added dropwise to a cold (0° C.)suspension of 3-(2-bromoacetyl)pyridine hydrobromide (10.6 g, 38.0 mmol)in tetrahydrofuran (70 mL) over a period of 10 minutes. After theaddition the mixture was stirred at room temperature, under a nitrogenatmosphere, overnight. The reaction was cooled to 0° C. and quenchedwith hydrogen chloride (0.5 M in methanol, 9 mL). The mixture wasfurther diluted with water and extracted with ethyl acetate. Theextracts were washed with water and dried with MgSO₄. Evaporation andpurification by flash column chromatography (dichloromethane/methylalcohol 95/5) gave (1R)-2-bromo-1-(3-pyridinyl)-1-ethanol as a brown oil(2.01 g, 27% yield). This oil was dissolved in tetrahydrofuran (18 mL)and then sodium hydroxide (5N, 35 mL) was added. The solution wasstirred at room temperature for 10 minutes. The mixture was diluted withwater and extracted with dichloromethane. The extracts were washed withwater, dried with magnesium sulfate. The extracts were concentrated togive the title compound as a white solid (1.01 g, 84% yield); ¹H NMR(300 MHz, DMSO-d₆) δ2.93-2.97 (m, 2 H), 3.14-3.17 (m, 2 H), 3.99-4.01(m, 2 H), 7.36-7.40 (m, 1 H), 7.63-7.66 (m, 1 H), 8.51-8.55 (m, 3 H); MS(ES) m/z: 122 (MH⁺).

EXAMPLE 130 (1S)-2-Amino-1-(3-pyridinyl)-1-ethanol

[0486] The title compound was prepared from 3-[(2S)-oxiranyl]pyridine(which was obtained in Example 129) and saturated ammonium methanol insubstantially the same manner, as described in Example 124. The productwas obtained as a brown oil; ¹H NMR (400 MHz, DMSO-d₆) δ1.60 (brs, 2 H),2.59-2.71 (m, 2 H), 4.47-4.50 (m, 1 H), 5.20 (brs, 1 H), 7.31-7.34 (m, 1H), 7.68-7.71 (m, 1 H), 8.42-8.43 (m, 1 H), 8.50-8.51 (m, 1 H); MS (ES)m/z: 139 (MH⁺).

EXAMPLE 1315-{4-[4-((2S)-2-Hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione

[0487] The title compound was prepared from(1S)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example130) and5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which wasobtained in Example 38) in substantially the same manner, as describedin Example 125. The product was obtained as a yellow solid; mp:>88° C.decomposed; ¹H NMR (400 MHz, DMSO-d₆) δ1.38-1.50 (m, 2 H), 1.90-1.98 (m,2 H), 2.63-2.71 (t, 2 H), 2.78-2.96 (m, 4 H), 3.23-3.27 (m, 1 H),3.62-3.65 (m, 2 H), 4.62-4.67 (m, 1 H), 4.76-4.79 (m, 1 H), 6.83-6.86(d, 2 H), 7.03-7.05 (d, 2 H), 7.36-7.38 (m, 1 H), 7.76-7.79 (m, 1 H),8.46-8.48 (m, 1 H), 8.57-8.58 (m, 1 H); MS (ES) m/z: 427 (MH⁺); Anal.Calcd. for C₂₂H₃₆N₄O₂×0.3 H₂O×0.3 CH₂Cl₂: C, 55.87; H, 5.51; N, 11.69.Found: C, 55.92; H, 5.80; N, 11.45.

EXAMPLE 132(1R)-2-Amino-1-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-yl-1-ethanol

[0488] The title compound was prepared from6-[(2R)oxiranyl][1,2,3,4]tetraazolo[1,5-a]pyridine and saturatedammonium methanol in substantially the same manner, as described inExample 124. The product was obtained as an off-white solid; mp 153-154°C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.60 (brs, 2 H), 2.73-2.84 (m, 2 H),4.65-4.68 (m, 1 H), 5.70 (brs, 1 H), 7.83-7.87 (m, 1 H), 8.14-8.16 (m, 1H), 9.08-9.09 (m, 1 H); MS (ES) m/z: 180 (M+H).

EXAMPLE 1335-(4-{4-[(2S)-2-(6-Amino-pyridin-3-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dionehydrochloride

[0489]5-[4-(4-{[(2R)-2-Hydroxy-2-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-ylethyl]amino}-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dionewas prepared from(1R)-2amino-1-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-yl-1-ethanol (whichwas obtained in Example 132) and5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which wasobtained in Example 38) in substantially the same manner, as describedin Example 125. The product was obtained as a yellow solid; mp: 130-132°C. This solid was dissolved in concentrated aqueous hydrochloric acid(0.3 mL) and methyl alcohol (2 mL). Tin chloride (0.196 g, 0.87 mmol)was added to the solution at room temperature. The mixture was thenstirred at reflux for 2 hours. Evaporation and purification by flashcolumn chromatography (dichloromethane/methyl alcohol 7/3)] gave ayellow solid. This solid was further purified by reverse phase HPLC togive a yellow solid (0.117 g, 61% yield); mp 182° C. (decomposed); ¹HNMR (400 MHz, DMSO-d₆) δ1.90 (brs, 2 H), 2.21 (brs, 2 H), 3.03-3.36 (m,8 H), 3.75-3.79 (m, 1 H), 4.86-4.90(m, 1 H), 4.98-5.01 (m, 1 H),7.03-7.05 (m, 1 H), 1.20 (brs, 4 H), 7.95-7.99 (m, 2 H), 8.21 (brs, 1H), 9.13 (brs, 1 H), 9.45 (brs, 1 H), 12.04 (brs, 1 H), 14.13 (brs, 1H); MS (ES) m/z: 442 (MH⁺).

EXAMPLE 134 3-[(2R)-Oxiranyl]pyridine

[0490] The title compound was prepared from(R)-2-methyl-CBS-oxazaborolidine monohydrate and3-(2-bromoacetyl)pyridine hydrobromide in substantially the same manner,as described in Example 123. The product was obtained as an oil; ¹H NMR(300 MHz, DMSO-d₆) δ2.94-2.97 (m, 1 H), 3.14-3.17 (m, 1 H), 3.99-4.01(m, 1 H), 7.36-7.40 (m, 1 H), 7.63-7.66 (m, 1 H), 8.51-8.55 (m, 2 H); MS(ES) m/z: 121 (M⁺).

EXAMPLE 135 (1R)-2-Amino-1-(3-pyridinyl)-1-ethanol

[0491] The title compound was prepared from 3-[(2R)-oxiranyl]pyridine(which was obtained in Example 134) and saturated ammonium methanol insubstantially the same manner, as described in Example 124. The productwas obtained as a brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ1.70 (brs, 2 H),2.62-2.74 (m, 2 H), 4.46-4.50 (m, 1 H), 5.20 (brs, 1 H), 7.30-7.34 (m, 1H), 7.68-7.71 (m, 1 H), 8.42-8.50 (m, 2 H); MS (ES) m/z: 139 (MH⁺).

EXAMPLE 1365-{4-[4-((2R)-2-Hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione

[0492] The title compound was prepared from(1R)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example135) and5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which wasobtained in Example 38) in substantially the same manner, as describedin Example 125. The product was obtained as a yellow solid; mp 87° C.(decomposed); ¹H NMR (400 MHz, DMSO-d₆) δ1.38-1.43 (m, 2 H), 1.89-1.91(m, 2 H), 2.62-2.71 (t, 2 ), 2.71-2.91 (m, 4 H), 3.23-3.27 (m, 1 H),3.60-3.63 (m, 2 H), 4.58-4.61 (m, 1 H), 4.72-4.75 (m, 1 H), 6.38-6.85(d, 2 H), 7.02-7.05 (d, 2 H), 7.34-7.37 (m, 1 H), 7.75-7.78 (m, 1 H),8.45-8.46 (m, 1 H), 8.56-8.57 (m, 1 H); MS (ES) m/z: 427 (MH⁺).

EXAMPLE 137 N-[5-(2-Bromoacetyl)-2-pyridinyl]methanesulfonamide

[0493] A solution of methane sulfonyl chloride (7.5 mL, 96.80 mmol) indichloromethane (50 mL) was added dropwise into a cold (−78° C.)solution of 1-(6-amino-3-pyridinyl)-1-ethanone (3.29 g, 24.20 mmol) andN,N-diisopropylethylamine (4.20 mL, 96.80 mmol) indichloromethane/acetonitrile (1/1, 250 mL) over a period of 30 minutes.After the addition the dry-ice bath was removed and reaction mixture waswarmed gradually to room temperature. After stirring at room temperaturefor 2 days, the mixture was evaporated and purified by flash columnchromatography (hexanes/ethyl acetate 3/7) to give a grey solid (1.0 g,19% yield). This solid (0.9 g, 4.2 mmol) was added portionwise to a roomtemperature stirred solution of 5,5-dibromobarbituric acid (2.17 g, 7.35mmol) in tetrahydrofuran (18 mL). After stirred at 60° C. for 6 hoursthe mixture was evaporated and purified by flash column chromatography(hexanes/ethyl acetate 1/1) to give an off-white solid (1.03 g, 84%yield); ¹H NMR (400 MHz, DMSO-d₆) δ3.33 (s, 3 H), 4.87 (s, 2 H),7.04-7.07 (m, 1 H), 8.20-8.23 (m, 1 H), 8.87 (s, 1 H); MS (ES) m/z: 292(M⁺); Anal. Calcd. for C₈H₉BrN₂O₃S: C, 32.78; H, 3.09; N, 9.56. Found:C, 33.27; H, 2.92; N, 9.60.

EXAMPLE 138N-[5-(2-{1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}1-1-hydroxy-ethyl)-pyridin-2-yl]-methanesulfonamide

[0494] Sodium borohydride (0.09 g, 2.34 mmol) was added portionwise intoa cold (0° C.) solution ofN-[5-(2-bromoacetyl)-2-pyridinyl]methanesulfonamide (which was obtainedin Example 137)(0.91 g, 3.12 mmol) in THF (15 mL). After the mixture wasstirred at 0° C. for 1.5 hours, the mixture was evaporated and purifiedby flash column chromatography (dichloromethane 95/5) to give anoff-white solid (0.66 g, 72%). A mixture of this solid (0.44 g, 1.54mmol), sodium iodide (0.23 g, 1.54 mmol) and sodium azide (0.41 g, 6.16mmol) in dimethyl sulfoxide (4 mL) was stirred at room temperature for 3days. The mixture was purified by flash column chromatography(hexanes/ethyl acetate 1/3) to give an oil. This oil was dissolved inmethyl alcohol (25 mL) and 10% Pd-C. The mixture was hydrogenated togive N-[5-(2-amino-1-hydroxyethyl)-2-pyridinyl]methanesulfonamide as anoil. This oil was treated with5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which wasobtained in Example 38) in substantially the same manner, as describedin Example 125, to give the title compound as a white solid; mp 57-59°C.; ¹H NMR (400 MHz, DMSO-d₆) δ1.20-1.31 (m, 2 H), 1.55-1.64 (m, 2 H),2.01-2.08 (m, 2 H), 3.60-3.71 (t, 2 H), 3.93-3.42 (m, 6 H), 3.71-3.75(m, 2 H), 4.77-4.87 (m, 2 H), 6.86-6.88 (d, 2 H), 6.98-7.00 (m, 1 H),7.05-7.07 (d, 2 H), 7.75-7.77 (m, 1 H), 8.22-8.23 (m, 1 H); MS (ES) m/z:520 (MH⁺); Anal. Calcd. for C₂₃H₂₉N₅O₅S₂×3 CF₃COOH: C, 40.42; H, 3.74;N, 8.13. Found: C, 40.15; H, 4.06; N, 8.10.

EXAMPLE 139 2-Methyl-5-oxiranylmethoxy-1H-indole-3-carboxylic acid ethylester

[0495] A solution of 2.19 g (10 mmol) of ethyl5-hydroxy-2-methyl-indole-3-carboxylate, 2.6 g (10 mmol) of 2S(+)glycidyl-3-nitrobenzenesulfonate and 1.5 g (11 mmol) of potassiumcarbonate in 25 mL reagent grade acetone was refluxed overnight. Themixture was then allowed to cool to room temperature and the solids wereremoved by vacuum filtration. The filtrate was concentrated in vacuo andthe residue was dissolved in ethyl acetate. The organics were washedonce with water, twice with brine, dried over sodium sulfate andconcentrated in vacuo. Then the solid was dried under vacuum to give2.65 g of the title compound as a dull tan solid; mp 93-94° C.; ¹H NMR(300 MHz, CDCl₃) δ1.44 (t, J=5.3 Hz, 3H), 2.71 (s, 3H), 2.74-2.80 (m,1H), 2.92 (t, J=4.7 Hz, 1H), 3.37-3.43 (m, 1H), 4.00-4.06 (m, 1 H),4.27-4.31 (m, 1H), 4.37 (q, J=5.3 Hz, 2H), 6.86 (dd, J=5.5, 3.0 Hz, 1H),7.18 (d, J=8.7 Hz, 1H), 7.67 (d, J=3.0 Hz, 1H), 8.32 (s, 1H); MS (ES)m/z: 275.9 (MH⁺); HRMS Calcd. for C₁₅H₁₈NO₄(MH⁺): 276.1236. Found:276.1228.

EXAMPLE 1405-((2S)-3-Azido-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acidethyl ester

[0496] A solution of 1.4 g (5.1 mmol) of2-methyl-5-oxiranylmethoxy-1H-indole-3-carboxylic acid ethyl ester(which was obtained in Example 139), 0.5 g (7.6 mmol) of sodium azideand 0.43 g (10.2 mmol) of lithium chloride in 15 mL anhydrous DMF washeated at 60° C. overnight. The mixture was cooled to room temperatureand quenched with water. The aqueous mixture was extracted with ethylacetate. The organic layer was washed twice with water, dried oversodium sulfate and concentrated in vacuo. The residue was then purifiedby flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes)to give 0.63 g of the title compound as a yellow solid; mp 75-77° C.; ¹HNMR (300 MHz, DMSO-d₆) δ1.34 (t, J=7.1 Hz, 3H), 2.66 (s, 3H), 3.42 (d,4.6 Hz, 1H), 3.89-3.95 (m, 2H), 4.00-4.06 (m, 1H), 4.26 (q, J=7.1 Hz,2H), 5.55 (d, J=5.1 Hz, 2H), 6.76 (dd, J=8.7, 2.7 Hz, 1H), 7.24 (d,J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 11.65 (s, 1H); MS (ES) m/z: 319.0(MH⁺); HRMS Calcd. for C₁₅H₁₈N₄O₄(M⁺): 318.1328. Found: 318.1334.

EXAMPLE 1415-((2S)-3-Amino-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acidethyl ester

[0497] A solution of 0.56 g (1.76 mmol) of5-((2S)-3-azido-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acidethyl ester (which was obtained in Example 140) and 1.2 g oftriphenylphosphine polymer resin (3 mmol/g) was stirred in 15 mL toluenefor 1.5 hours under nitrogen. The resin was collected by filtration andwashed twice with 25 mL of toluene. The resin was then stirred in 60 mLof 9:1 THF/methanol for four hours. The resin was removed by vacuumfiltration and washed with 9:1 THF/methanol. The filtrate wasconcentrated in vacuo. Then the solid was dried under vacuum to give0.52 g of the title compound as a beige solid; mp 66-68° C.; ¹H NMR (300MHz, DMSO-d₆) δ1.32-1.37 (m, 3H), 1.80 (brs, 1H), 2.61 (s, 3H),2.69-2.75 (m, 2H), 3.69-3.76 (m, 1H), 3.82-3.95 (m, 2H), 4.23 (q, J=6.93Hz, 2H), 4.90 (brs, 1H), 6.76 (dd, J=2.52 Hz, 8.73 Hz, 1H), 7.23 (d,J=8.7 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 8.85 (brs, 1H), 11.65 (s, 1H); MS(ES) m/z: 293.0 (MH⁺); HRMS Calcd. for C₁₅H₂₁N₂O₄(MH⁺): 293.1501. Found:293.1498.

EXAMPLE 1425-(3{-1-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-2-fluoro-phenyl]-piperidin-4-ylamino}-(2S)-2-hydroxy-propoxy)-2-methyl-1H-indole-3carboxylicacid ester

[0498] The title compound was prepared from5-((2S)-3-amino-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylic acidethyl ester (which was obtained in Example 141) and5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione(which was obtained in Example 61) according to the procedure of Example73 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.34 (t, J=7.1 Hz, 3H),1.56-1.63 (m, 2H), 2.03 (m, 2H), 2.61 (s, 3H), 2.67-2.75 (m, 4H),2.88-2.96 (m, 4H), 3.04-3.07 (m, 2H), 3.95-3.97 (m, 2H), 4.05 (m, 2H),4.25 (q, J=7.1 Hz, 2H), 4.61-4.66 (m, 1H), 5.52 (brs, 1H), 6.79 (dd,J=8.7, 2.5 Hz, 1H), 6.94-7.03 (m, 2H), 7.24-7.29 (m, 2H), 7.46 (d, J=2.3Hz, 1H) 11.65 (s, 1H); MS (ES) m/z: 599.1 (MH⁺); HRMS forC₃₀H₃₆FN₄O₆S(MH⁺): 599.2339. Found: 599.2333.

EXAMPLE 1431-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione

[0499] A mixture of methyl 4-fluorobenzoyl acetate (2.06 g, 10 mmol),1,4-dioxa-8-aza-spiro[4.5]decane (2.19 g, 15 mmol), and pottassiumcarbonate (1.66 g, 12 mmol) in 3 mL of1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone was stirred at 60° C.for 3 days. It was then diluted with water and the gummy precipitate waswashed with water, ether, and ethyl acetate-ether (1:5), and then driedin vacuo to give 0.98 g yellow solid; ¹H NMR (300 MHz, CDCl₃) δ1.66-1.72(dd, 4 H), 1.77-1.81 (d, 4 H), 3.51-3.55 (m, 4 H), 3.57-3.61 (m, 2 H),3.70-3.741 (m, 2 H), 3.96 (s, 4 H), 4.00 (s, 4 H), 4.03 (s, 2 H), 6.68(d, 2 H), 7.94 (d, 2 H); MS (ES) m/z: 431 (MH⁺).

EXAMPLE 1445-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-1,2-dihydro-pyrazol-3-one

[0500]1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione(which was obtained in Example 143)(0.43 g, 1 mmol) was dissolve in amixture of ethanol (10 mL) and tetrahydrofuran (4 mL). The solution wastreated with 0.08 mL (2.4 mmol) of hydrazine and heated at reflux for 4days. After cooling to room temperature, the resulting suspension wasfiltered, and the precipitate was washed with ethanol and dried in vacuoto give 0.24 g of light yellow solid; ¹H NMR (DMSO-d₆) δ1.67-1.71 (t, 4H), 3.29-3.32 (t, 4 H), 3.91 (s, 4 H), 5.72 (s, 1 H), 6.97 (d, 2 H),7.48 (d, 2 H), 9.50 (brs, 1 H), 11.80 (brs, 1 H); MS (ES) m/z: 302(MH⁺).

EXAMPLE 1451-[4-(5-Oxo-2,5-dihydro-1H-pyrazol-3-yl)-phenyl]-piperidin-4-one

[0501] To a suspension of5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-1,2-dihydro-pyrazol-3-one(which was obtained in Example 144)(0.15 g, 0.5 mmol) in acetone (5 mL)was added 5 mL of 10% sulfuric acid. The resulting solution was stirredat room temperature for 4 days. Water (5 mL) was then added, and theacetone was evaporated. The aqueous residue was treated with sodiumcarbonate until pH 8, and the resulting suspension was filtered. Theprecipitate was washed with water and ether, and dried in vacuo to give0.15 g of tan solid; ¹H NMR (DMSO-d₆) δ2.41 (t, 4 H), 3.64 (t, 4 H),5.74 (s, 1 H), 7.04 (d, 2 H), 7.53 (d, 2 H), 9.55 (brs, 1 H), 11.80(brs, 1 H); MS (ES) m/z: 258 (MH⁺).

EXAMPLE 146N-[(2R)-2-Hydroxy-5-(1-hydroxy-2-(1-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide

[0502] The title compound was prepared from1-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)-phenyl]-piperidin-4-one (whichwas obtained in Example 145)(0.13 g, 0.5 mmol) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(0.15 g, 0.6 mmol) which was obtained in Example 10)according to theprocedure shown for Example 73 to give 0.14 g of orange solid; mp225-227° C.; ¹H NMR (DMSO-d₆) δ1.15-1.20 (m, 2 H), 1.87-1.99 (m, 2 H),2.64-2.75 (m, 5 H), 2.92 (s, 3 H), 3.66 (m, 2 H), 4.49 (m, 2 H), 5.71(s, 1 H), 6.82 (d, 2H), 6.93 (d, 2 H), 7.02 (dd, 2 H), 7.19 (d, 2 H),7.47 (d, 2 H); MS (ES) m/z: 488 (MH⁺). EXAMPLE 147

4-(4-Oxo-1-piperidin-1-yl)benzamide

[0503] A suspension of4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)benzonitrile (Taylor, E. C.,Skotnicki, J. S. Synthesis, 1981, 606)(15 g, 61.5 mmol) in 150 mL ofconcentrated hydrochloric acid was stirred at room temperatureovernight. The solution was neutralized with 5N sodium hydrochloride andthe solid that formed was collected to give the title compound as awhite solid; ¹H NMR (300 MHz, CDCl₃) δ2.58 (t, J=6.1 Hz, 4 H), 3.74 (t,J=6.1 Hz, 4 H), 5.76 (brs, 2 H), 6.94 (d, J=9.0 Hz, 2 H), 7.74 (d, J=9.0Hz, 2 H); MS (ES) m/z: 218.8 (MH⁺); HRMS Calcd. for C₁₂H₁₄N₂O₂:218.1055. Found: 218.1051

EXAMPLE 148 [4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-methanol

[0504] Sodium borohydride (3.78 g, 100 mmol) was added in four portionsto a stirred solution of4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde (4.94 g, 20 mmol)(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) inmethanol/tetrahydrofuran (1:1, 100 mL) at 0° C. and the resultingsolution was stirred at 0° C. for 30 minutes and then at roomtemperature for 1 hour. Methylene chloride was added and the solutionwas washed with water and dried over sodium sulfate. The solvents wereremoved and the residue was solidified upon standing (5.0 g, 100%); ¹HNMR (300 MHz, CDCl₃) δ1.84 (t, J=5.7 Hz, 4 H), 3.33 (t, J=5.7 Hz,3.99(s, 4 H), 4.59 (d, J=5.8 Hz, 2 H), 6.93 (d, J=8.7 Hz, 2 H), 7.24 (d,J=8.7 Hz, 2 H); MS (ES) m/z: 249.9 (MH⁺); HRMS Calcd. forC₁₄H₂₀NO₃(MH⁺): 250.1443. Found: 250.1434.

EXAMPLE 149 [4-(4-Oxo-piperidin-1-yl)-phenyl]-acetic acid

[0505] 1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-ethanone (2.61g, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) wasadded to a solution of thallium trinitrate trihydrate (4.44 g, 10mmol)(McKillop, A., Swann, B. P., Taylor, E. C. J. Am. Chem. Soc., 1971,93, 4919) in methanol (40 mL) and methylene chloride (20 mL) containingperchloric acid (70%, 10 mL). After 5 hours at room temperature theprecipitated thallium (I) nitrate was removed by filtration, and thefiltrate was diluted with water (100 mL). The organic phase wasseparated, the aqueous layer was extracted with methylene chloride, andthe combined organic phases were washed with water, dried over sodiumsulfate and concentrated. The residue was dissolved in concentratedhydrochloric acid (250 mL) at room temperature. After 3 hours thesolution pH was adjusted to 5 by ˜28% ammonium hydroxide. The aqueouslayer was extracted with methylene chloride, and the combined organicphases were washed with water, dried over sodium sulfate andconcentrated. The product was purified by chromatography on silica gelwith ethyl acetate/hexanes eluant to give the title compound as a paleyellowish solid (0.4 g, 17%); ¹H NMR (300 MHz, DMSO-d₆) δ2.42 (t, J=6.0Hz, 4 H), 3.41 (s, 2 H), 3.56 (t, J=6.0 Hz, 4 H), 6.98 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2 H), 12.20 (s, 1 H); MS (ES) m/z: 234.3 (MH⁺);HRMS Calcd. for C₁₃H₁₅NO₃(M⁺): 233.1052. Found: 233.1045.

EXAMPLE 150 4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid

[0506] A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acidethyl ester (14 g, 48.1 mmol) (Taylor, E. C., Skotnicki, J. S.Synthesis, 1981, 606) in methanol/tetrahydronfuran (1:1, 100 mL) andsodium hydroxide (2 N, 150 mL) was refluxed for 2 hours. After coolingto room temperature the solution was acidified by acetic acid and thesolid which was formed was collected and dried to give the titlecompound as a white solid (12.5 g, 99%); ¹H NMR (300 MHz, CDCl₃) δ1.67(t, J=5.6 Hz, 4 H), 3.43 (t, J=5.6 Hz, 4 H), 3.92 (s, 4 H), 6.96 (d,J=9.0 Hz, 2 H), 7.75 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 264.4 (MH⁺); HRMSCalcd. for C₁₄H₁₇NO₄(M⁺): 263.1158. Found: 263.1160.

EXAMPLE 151 4-(4-Oxo-piperidin-1-yl)-benzoic acid

[0507] 4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid(which wasobtained in Example 150)(12.5 g, 47.5 mmol) was treated withconcentrated hydrochloric acid (500 mL) at room temperature. After 15hours ˜28% ammonium hydroxide was added dropwise and the precipitate wascollected by filtration, and dried over phosphorus pentoxide to give thetitle compound as a white solid (9.2 g, 88%); ¹H NMR (300 MHz, CDCl₃)δ2.46 (t, J=6.1 Hz, 4 H), 3.74 (t, J=6.1 Hz, 4 H), 7.02 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.0 Hz, 2 H); MS ES) m/z: 219.8 (MH⁺); HRMS Calcd. forC₁₂H₁₄NO₃(MH⁺): 220.0974. Found: 220.0947.

EXAMPLE 1522-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-malonic aciddiethyl ester

[0508] A solution of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde(2.47, 10 mmol)(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606)and diethyl malonate (2.0 g, 12.5 mmol) in toluene (100 mL) containing acatalytic quantity of piperidinum acetate was refluxed for 18 hours.After cooling to room temperature the solution was washed with water,dried over sodium sulfate and concentrated. Purification by columnchromatography on silica gel using ethyl acetate/hexanes as the eluentgave the title compound as a yellowish gum; ¹H NMR (300 MHz, CDCl₃)δ1.28 (t, J=7.1 Hz, 3 H), 1.29 (t, J=7.1 Hz, 3 H), 1.79 (t, J=5.8 Hz, 4H), 3.46 (t, J=5.8 Hz, 4 H), 4.27 (q, J=7.1 Hz, 2 H), 4.31 (q, J=7.1 Hz,2 H), 6.85 (d, J=8.9 Hz, 2 H), 7.33 (d, J=8.9 Hz, 2 H), 7.61(s, 1 H); MS(ES) m/z: 390.0 (MH⁺); HRMS Calcd. for C₂₁H₂₇NO₆(MH⁺): 390.1911. Found:390.1910.

EXAMPLE 153 2-[4-(4-Oxo-piperidin-1-yl)-benzylidene]-malonic aciddiethyl ester

[0509] The title compound was prepared from2-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-malonic aciddiethyl ester (which was obtained in Example 152) according to theprocedure of Example 147 as a yellowish gum; ¹H NMR (300 MHz, CDCl₃)δ1.20-1.40(m, 6 H), 2.56 (t, J=6.1 Hz, 4 H), 3.73(t, J=6.1 Hz, 4 H),4.28 (q, J=7.1 Hz, 2 H), 4.46 (q, J=7.1 Hz, 2 H), 6.90 (d, J=8.9 Hz, 2H), 7.41 (d, J=8.9 Hz, 2 H), 7.41 (s, 1 H); MS (ES) m/z: 345.9 (MH⁺);HRMS Calcd. for C₂₁H₂₇NO₆(MH⁺): 346.1649. Found: 346.1647.

EXAMPLE 154 N-(Benzyloxy)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzamide

[0510] A mixture of 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzoic acid(which was obtained in Example 150)(1.58 g, 6 mmol),1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.34 g, 7mmol) and O-benzylhydroxyamine hydrochloride (1.05 g, 6.6 mmol) wasstirred in methylene chloride (150 mL). N-methylmorpholine (1.82 g, 18mol) was added dropwise and the mixture was stirred overnight. Themixture was then washed with 0.05 N hydrochloric acid and water. Theresulting solution was dried with magnesium sulfate and concentrated.The residue was crystallized from methylene chloride/hexanes to give thetitle compound as a white solid; ¹H NMR (300 MHz, CDCl₃) δ1.67 (t, J=5.6Hz, 4 H), 3.42(t, J=5.6 Hz, 4 H), 3.91(s, 4 H), 4.89(s, 2 H), 6.97 (d,J=9.0 Hz, 2 H), 7.30-7.50(m, 5 H), 7.62 (d, J=9.0 Hz, 2 H); MS (ES) m/z:369.3 (MH⁺); HRMS Calcd. for C₂₁H₂₄N₂O₄(M⁺): 368.1736. Found: 368.1744.

EXAMPLE 155 N-(Benzyloxy)-4-(4-oxo-piperidin-yl)benzamide

[0511] The title compound was prepared fromN-(benzyloxy)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzamide (which wasobtained in Example 154) according to the procedure of Example 147 as agrey solid; ¹H NMR (300 MHz, CDCl₃) δ2.41 (t, J=6.0 Hz, 4 H), 3.71(t,J=6.0 Hz, 4 H), 4.89(s, 2 H), 7.19 (d, J=9.0 Hz, 2 H), 7.30-7.50(m, 5H), 7.67(d, J=9.0 Hz, 2 H), 11.50 (s, 1 H); MS (ES) m/z: 325.4 (MH⁺);HRMS Calcd. for C₁₉H₂₁N₂O₃(MH⁺): 325.1552. Found: 325.1540.

EXAMPLE 156 (2S)-2-[4-(4-Oxo-piperidin-1-yl)-benzoylamino]-pentanedioicacid dibenzyl ester

[0512] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-glutamic acid dibenzyl ester p-tosylate according to theprocedure of Example 154 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.90-2.20 (m, 4 H), 2.42 (t, J=6.0 Hz, 4 H), 3.72(t, J=6.0 Hz, 4 H),4.45-4.55(m, 1 H), 5.07(s, 2 H), 5.13(s, 2 H), 7.03 (d, J=9.0 Hz, 2 H),7.25-7.40(m, 5 H), 7.85(d, J=9.0 Hz, 2 H), 8.49(d, J=9.0 Hz, 2 H); MS(ES) m/z: 529.1 (MH⁺); HRMS Calcd. for C₃₁H₃₃N₂O₆(MH⁺): 529.2339. Found:529.2331.

EXAMPLE 157 (2S)-2-[4-(4-Oxo-piperidin-1-yl)-benzoylamino]-pentanedioicacid diethyl ester

[0513] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-glutamic acid diethyl ester hydrochloride according to theprocedure of Example 154 as a yellowish gum; ¹H NMR (300 MHz, CDCl₃)δ1.22 (t, J=7.1 Hz, 3 H), 1.31 (t, J=7.1 Hz, 3 H), 2.10-2.50 (m, 4 H),2.57 (t, J=6.1 Hz, 4 H), 3.73(t, J=6.1 Hz, 4 H), 4.10-4.30(m, 4 H),4.70-4.85(m, 1 H), 6.90 (d, J=7.5 Hz, 1 H), 7.08(d, J=8.9 Hz, 2 H),7.78(d, J=8.9 Hz, 2 H); MS (ES) m/z: 405.3 (MH⁺).

EXAMPLE 158 3-[4-(4-Oxo-piperidin-1-yl)-benzoylamino]-propionic acidethyl ester

[0514] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and beta-alanine ethyl ester hydrochloride according to theprocedure of Example 154 as a yellowish solid; ¹H NMR (300 MHz, CDCl₃)δ1.28 (t, J=7.1 Hz, 3 H), 2.56 (t, J=6.1 Hz, 4 H), 2.64 (t, J=5.7 Hz, 2H), 3.55-3.65 (m, 6 H), 4.15(q, J=7.1 Hz, 2 H), 6.82 (t, J=5.7 Hz, 1 H),6.95(d, J=8.9 Hz, 2 H), 7.70(d, J=8.9 Hz, 2 H); MS (ES) m/z: 319.1(MH⁺).

EXAMPLE 159 3-[4-(4-Oxo-piperidin-1-yl)-benzoylaminol]propionic acidbenzyl ester

[0515] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and beta-alanine benzyl ester p-tosylate according to the procedureof Example 154 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.42 (t,J=6.0 Hz, 4 H), 2.63 (t, J=6.9 Hz, 2 H), 3.40-3.50(m, 2 H), 3.71(t,J=6.0 Hz, 4 H), 5.10(s, 2 H), 6.74 (d, J=8.9 Hz, 2 H), 7.30-7.40(m, 5H), 7.73(d, J=8.9 Hz, 2 H), 8.29(t, J=5.5 Hz, 1 H); MS (ES) m/z: 381.3(MH ⁺); HRMS Calcd. for C₂₂H₂₄N₂O₄(M⁺): 380.1737. Found: 380.1755.

EXAMPLE 1601-[4-(4-Oxo-piperidin-1-yl)-benzoyl]pyrrolidine-(2S)-2-carboxylic acidmethyl ester

[0516] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid(which was obtained in Example 151)and L-proline methyl ester hydrochloride according to the procedure ofExample 154 as a pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.70-1.95(m, 4 H), 2.20-2.40(m, 1 H), 2.41 (t, J=6.0 Hz, 4 H), 3.32(s,3 H), 3.69. (t, J=6.0 Hz, 4 H), 4.35-4.50(m, 2 H), 7.01 (d, J=8.7 Hz, 2H), 7.49(d, J=8.7 Hz, 2 H); MS (ES) m/z: 331.2 (MH⁺); HRMS Calcd. forC₁₈H₂₂N₂O₄(M⁺): 330.1580. Found: 330.1572.

EXAMPLE 161 Ethyl {[4-(4-oxo-1-piperidinyl)benzoyl]amino}acetate

[0517] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and glycine ethyl ester hydrochloride according to the procedure ofExample 154 as a pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20(t, J=7.1 Hz, 3 H), 2.43 (t, J=6.1 Hz, 4 H), 3.72 (t, J=6.1 Hz, 4 H),3.95 (d, J=5.8 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 7.04 (d, J=8.9 Hz, 2H), 7.77(d, J=8.9 Hz, 2 H), 8.63 (t, J=5.8 Hz, 1 H); MS (ES) m/z: 305.2(MH⁺); HRMS Calcd. for C₁₈H₂₂N₂O₄(M⁺): 304.1423. Found: 304.1422.

EXAMPLE 162 Methyl {[4-(4-oxo-1-piperidinyl)benzoyl]amino}acetate

[0518] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and glycine methyl ester hydrochloride according to the procedureof Example 154 as a gum; MS (ES) m/z: 291.3 (MH⁺).

EXAMPLE 1633-Methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-butyric acidethyl ester

[0519] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-valine ethyl ester hydrochloride according to the procedureof Example 154 as a pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ0.93 (d, J=6.8 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 1.20 (t, J=7.1 Hz, 3H), 2.10-2.30 (m, 1 H), 2.43 (t, J=6.0 Hz, 4 H), 3.72 (t, J=6.0 Hz, 4H), 4.00-4.30(m, 4 H), 4.46 (t, J=5.1 Hz, 1 H), 7.05 (d, J=8.9 Hz, 2 H),7.82(d, J=8.9 Hz, 2 H), 8.21 (d, J=7.9 Hz, 1 H); MS (ES) m/z: 347.3(MH⁺); HRMS Calcd. for C₁₉H₂₆N₂O₄(M⁺): 346.1892. Found: 346.1896.

EXAMPLE 164(2S)-2-[4-(4-Oxo-piperidin-1-yl)-benzoylamino]-3-phenyl-propionic acidmethyl ester

[0520] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-phenylalanine methyl ester hydrochloride according to theprocedure of Example 154 as a pale yellowish solid; ¹H NMR (300 MHz,DMSO-d₆) δ2.41 (t, J=6.0 Hz, 4 H), 3.05-3.20 (m, 2 H), 3.71 (t, J=6.0Hz, 4 H), 4.55-4.65(m, 1 H); 6.97 (d, J=8.9 Hz, 2 H), 7.10-7.45 (m, 5H), 7.73(d, J=8.9 Hz, 2 H), 8.52 (d, J=7.8 Hz, 1 H); MS (ES) m/z: 381.3(MH⁺); HRMS Calcd. for C₂₂H₂₅N₂O₄(MH⁺): 381.1809. Found: 380.1807.

EXAMPLE 1654-Methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanoic acidethyl ester

[0521] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-leucine ethyl ester hydrochloride according to the procedureof Example 154 as a white flake; ¹H NMR (300 MHz, CDCl₃) δ0.99(t, J=6.2Hz, 6 H), 1.30(t, J=7.1 Hz, 3 H), 1.60-1.80(m, 3 H), 2.56(t, J=6.0 Hz, 4H), 3.72(t, J=6.0 Hz, 4 H), 4.22(q, J=7.1 Hz, 2 H), 4.80-4.90(m, 1 H),6.42(d, J=8.2 Hz, 1 H), 6.94(d, J=7.0 Hz, 2 H), 7.77 (d, J=7.0 Hz, 1 H);MS (ES) m/z: 361.3 (MH⁺); HRMS Calcd. for C₂₀H₂₈N₂O₄(M⁺): 360.2049.Found: 360.2081.

EXAMPLE 1664-Methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzolamino]-pentanoic acidmethyl ester

[0522] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and L-leucine methyl ester hydrochloride according to the procedureof Example 154 as a gum; ¹H NMR (300 MHz, CDCl₃) δ0.96(t, J=6.2 Hz, 6H), 1.60-1.80(m, 3 H), 2.57(t, J=6.1 Hz, 4 H), 3.71(t, J=6.1 Hz, 4 H),3.77 (s, 3 H), 4.80-4.90(m, 1 H), 6.40(d, J=8.2 Hz, 1 H), 6.94(d, J=7.0Hz, 2 H), 7.75(d, J=7.0 Hz, 1 H); MS (ES) m/z: 347.4 (MH⁺); HRMS Calcd.for C₁₉H₂₆N₂O₄(M⁺): 346.1892. Found: 346.1881.

EXAMPLE 167 Methyl1-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-cyclopropanecarboxylate

[0523] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) and 1-aminocyclopropane-1-carboxylic acid methyl esterhydrochloride according to the procedure of Example 154 as a gum; MS(ES) m/z; 317.2 (MH⁺).

EXAMPLE 168(E)-3-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-acrylic acid ethylester

[0524] To a solution of lithium bromide (0.53 g, 6 mmol) intetrahydrofuran (5 mL) was added triethyl phosphonoacetate (1.14 g, 5mmol), followed by triethylamine (0.51 g, 5 mmol). After stirring for 10min, a solution of4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzaldehyde(Taylor, E. C.,Skotnicki, J. S. Synthesis, 1981, 606) (1.24 g, 5 mmol) intetrahydrofuran (2 mL) was added, and the mixture was stirred at roomtemperature for 20 hours. Additional triethyl phosphonoacetate (0.57 g,2.5 mmol) and triethylamine (0.25 g, 2.5 mmol) were then added, andstirring was continued for 3 days. The mixture was evaporated, and theresidue stirred with 20 mL of water and 5 mL of 1 N hydrochloric acid.The aqueous suspension was filtered, and the precipitate was washed withwater, and dried in vacuo to give 1.28 g of a light yellow solid; m.p.115-116° C.; ¹H NMR (CDCl₃) δ1.33 (t, 3 H), 1.81 (dd, 4 H), 3.47 (dd, 4H), 4.00 (s, 4 H), 4.25 (q, 2 H), 6.26 (d, 1 H), 6.89 (d, 2 H), 7.42 (d,2 H), 7.62 (d, 1 H); MS (ES) m/z: 318 (MH⁺).

EXAMPLE 169 (E)-3-[4-(4-Oxo-piperidin-1-yl)-phenyl]-acrylic acid ethylester

[0525] Prepared according to Example 151 from 0.63 g (2 mmol) of3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-acrylic acid ethylester(which was obtained in Example 168), yielding 0.37 g of lightyellow solid; m.p. 96-98° C.; ¹H NMR (CDCl₃) δ1.33(t, 3 H), 2.57 (t, 4H), 3.71 (t, 4 H), 4.25 (q, 2 H), 6.28 (d, 1 H), 6.93 (d, 2 H), 7.47 (d,2 H), 7.63 (d, 1 H); MS (ES) m/z: 274.3 (MH⁺).

EXAMPLE 170(E)-3-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-acrylic acid

[0526] A solution of 0.52 g (1.6 mmol) of3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-acrylic acid ethylester (which was obtained in Example 168)in tetrahydrofuran (3 mL) andethanol (2 mL) was treated with 5 mL of 1 N NaOH. After 18 h at roomtemperature, the mixture was acidified with acetic acid. The resultingsuspension was filtered and the precipitate was washed with water, anddried in vacuo to give 0.47 g of light yellow solid; m.p. 221-222° C.;¹H NMR (DMSO-d₆) δ1.67 (dd, 4 H), 3.40 (dd, 4 H), 3.91 (s, 4 H), 6.26(d, 1 H), 6.96 (d, 2 H), 7.47 (d, 1 H), 7.50 (d, 2 H), 12.10 (bs, 1 H);MS (ES) m/z: 290 (MH⁺).

EXAMPLE 171 (E)-3-[4-(4-Oxo-piperidin-1-yl)-phenyl]-acrylic acid

[0527] Prepared according to the procedure of Example 151 from 0.15 g(0.5 mmol) of 3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-acrylicacid which was obtained in Example 170), yielding 0.11 g of yellowsolid; m.p. 215° C.; ¹H NMR (DMSO-d₆) δ2.42 (t, 4 H), 3.71 (t, 4 H),6.28 (d, 1 H), 7.01 (d, 2 H), 7.50 (d, 1 H), 7.55 (d, 2 H); MS (ES) m/z:246.3 (MH⁺).

EXAMPLE 1724-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-benzamide

[0528] The title compound was prepared from4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtainedin Example 150) (0.53 g, 2 mmol) and (S)-leucinol (0.30 g, 2.5 mmol)according to the procedure shown for Example 154 to give 0.53 g of awhite solid; m.p. 90-91° C.; MS (ES) m/z: 363.3 (MH⁺); HRMS (ES) Calcd.for C₂₀H₃₁N₂O₄ (MH⁺): 363.2278, Found: 363.2275.

EXAMPLE 173N-[(1S)-1-(Hydroxymethyl)-3-methylbutyl]-4-(4-oxo-1-piperidinyl)benzamide

[0529] Prepared according to the procedure of Example 151 from 0.22 g(0.6 mmol) of4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzamide(which was obtained in Example 172), yielding 0.15 g of light yellowfoam; MS (ES) m/z: 319.3 (MH⁺); HRMS (ES) Calcd. for C₁₈H₂₇N₂O₃ (MH⁺):319.2016, Found: 319.2016.

EXAMPLE 1744-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-N-[(3S)-2-oxoazepanyl]benzamide

[0530] The title compound was prepared from4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtainedin Example 150) (0.26 g, 1 mmol) and L-α-amino-ε-caprolactam (0.20 g,1.5 mmol) according to the procedure shown for Example 154 to give 0.31g of a white solid; m.p. 185-186° C.; MS (ES) m/z: 374.3 (MH⁺); HRMS(El) Calcd. for C₂₀H₂₇N₃O₄ (M⁺): 373.2001, Found: 373.1995.

EXAMPLE 175 N-[(3S)-2-Oxoazepanyl]-4-(4-oxo-1-piperidinyl)benzamide

[0531] Prepared according to the procedure of Example 151 from 0.26 g(0.7 mmol) of4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-[(3S)-2-oxoazepanyl]benzamide(which was obtained in Example 174), yielding 0.19 g of a white solid;m.p. 177-179° C.; MS (ES) m/z: 330.3 (MH³⁰ ); HRMS (El) Calcd. forC₁₈H₂₃N₃O₃ (M⁺): 329.1740, Found: 329.1721.

EXAMPLE 176N-Butyl-N-(cyanomethyl)-4-(1,4-dioxa-8-azaspiro[4.51]dec-8-yl)benzamide

[0532] The title compound was prepared from4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoic acid (which was obtainedin Example 150) (0.37 g, 1.4 mmol) and (n-butylamino)acetonitrile (0.48g, 4.2 mmol) according to the procedure shown for Example 154 to give0.52 g of an amber gum; MS (ES) m/z: 358.3 (MH⁺); HRMS (ES) Calcd. forC₂₀H₂₈N₃O₃ (MH⁺): 358.2125, Found: 358.2120.

EXAMPLE 177N-Butyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-(1H-tetraazol-5-oxa-8-azaspiro[4.5]dec-8-yl)-N-(1H-tetraazol-5-ylmethyl)benzamide

[0533] To a solution ofN-butyl-N-(cyanomethyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)benzamide(which was obtained in Example 176) (0.36 g, 1 mmol) in N,N′-dimethylpropyleneurea (3 mL) was added sodium azide (0.20 g, 3 mmol)and tiethylamine hydrochloride (0.21 g, 1.5 mmol). The mixture wasstirred at 120° C. for 18 hours. It was then cooled to room temperature,diluted with water (30 mL), and saturated with sodium chloride. Theresulting mixture was extracted with dichloromethane, and passed througha pad of silica gel. The filter pad was first eluted with ethyl acetateand 5% methanol in ethyl acetate, followed by 25% methanol indichloromethane. Evaporation of solvents from the latter eluent andtrituration with dichlororhethane-ether gave 0.33 g of an off-whitesolid; m.p. 145-146° C.; MS (ES) m/z: 401.3 (MH⁺); HRMS (ES) Calcd. forC₂₀H₂₉N₆O₃ (MH⁺): 401.2296, Found: 401.2291.

EXAMPLE 178N-Butyl-4-(4-oxo-1-piperidinyl)-N-(1H-tetraazol-5-ylmethyl)benzamide

[0534] Prepared according to the procedure of Example 151 from 0.27 g(0.7 mmol) ofN-butyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-(1H-tetraazol-5-oxa-8-azaspiro[4.5]dec-8-yl)-N-(1-H-tetraazol-5-ylmethyl)benzamide(which was obtained in Example 177), yielding 0.18 g of a colorlessfoam; MS (ES) m/z: 357.4 (MH⁺); HRMS (ES) Calcd. for C₁₈H₂₅N₆O₂ (MH⁺):357.2034, Found: 357.2034.

EXAMPLE 179N-}4-[4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazole-4-yloxy)-propylamino]-piperidin-1-yl}-benzoicacid ethyl ester

[0535] A mixture of 1-(4-ethoxycarbonylphenyl)-4-piperidone (0.25 g, 1mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.22g, 1 mmol) U.S. Pat No. 5,786,356/1988) in 100 mL of ethanol and 0.5 mLof acetic acid was hydrogenated in the presence of 400 mg of 10%palladium on carbon under hydrogen (5˜20 psi) for overnight. Thecatalyst was then removed by filtering through a short pad of silicagel. The filtrate was concentrated and purified by thin layerchromatography (12% methanol/methylene chloride) to give the titlecompound as a white solid (0.22 g, 48%); mp>170° C. (decomposed); ¹H NMR(300 MHz, DMSO-d₆) δ1.28 (t, J=7.0 Hz, 3 H), 1.30-1.55 (m, 2 H),1.80-2.10 (m, 2 H), 2.80-3.10 (m, 5 H), 3.80-4.10 (m, 5 H), 4.23 (q,J=7.0 Hz, 2 H), 6.58 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.4 Hz, 1 H), 6.86(dd, J=8.4, 7.8 Hz, 1 H), 6.98 (d, J=8.6 Hz, 2 H), 7.77 (d, J=8.6 Hz, 2H), 10.60 (s, 1 H), 10.75 (s, 1 H); MS (ES) m/z: 455.1 (MH⁺); HRMSCalcd. for C₂₄H₃₀N₄O₅(MH⁺): 454.2216. Found: 454.2211.

EXAMPLE 180{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester

[0536] 1-(4-Ethoxycarbonylphenyl)-4-piperidone (Taylor, E. C.,Skotnicki, J. S. Synthesis, 1981, 606)(29 g, 1.2 mmol) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) (0.29 g, 1.2 mmol) were mixed indimethylformamide (10 mL) and then treated with sodiumtriacetoxyborohydride (1.01 g, 4.7 mmol) and acetic acid (0.5 mL). Afterstirring at room temperature under a nitrogen atmosphere for 15 hoursthe mixture was poured into a saturated aqueous sodium bicarbonate. Theprecipitate which was formed was collected and purified by silica gelchromatography (methanol/methylene chloride) to give the titled compoundas a white solid (0.28 g, 50%); mp>95° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.28 (t, J=7.1 Hz, 3 H), 1.30-1.55 (m, 2 H), 1.80-1.95 (m, 2H), 2.55-3.50 (m, 5 H), 2.92 (s, 3 H), 3.75-3.90 (m, 2 H), 4.22 (q,J=7.1 Hz, 2 H), 6.82 (d, J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 7.00(dd, J=8.2, 1.9 Hz, 1 H), 7.18 (d, J=1.9 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2H); MS (ES) m/z: 478.0 (MH⁺); HRMS Calcd. for C₂₃H₃₂N₃O₆S(MH⁺):478.2006. Found: 478.2000.

EXAMPLE 181{4-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester hydrochloride

[0537] The free base was prepared from1-(4-ethoxycarbonylphenyl)-4-piperidone (Taylor, E. C., Skotnicki, J. S.Synthesis, 1981, 606) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanolhydrochloride(which was obtained in Example 1) according to theprocedure of Example 180. The hydrochloride salt was produced by theaddition of hydrochloride gas as a white solid; mp>205° C. (decomposed);¹H NMR (300 MHz, DMSO-d₆) δ1.28 (t, J=7.1 Hz, 3 H), 1.55-1.75 (m, 2 H),2.05-2.25 (m, 2 H), 2.70-3.40 (m, 5 H), 3.95-4.10 (m, 2 H), 4.26 (q,J=7.1 Hz, 2 H), 5.00-5.10 (m, 1 H), 7.06 (d, J=9.0 Hz, 2 H), 7.30-7.60(m, 3 H), 7.80 (d, J=9.0 Hz, 2 H), 8.83 (br s, 1 H), 9.50 (br s, 1 H);MS (ES) m/z: 402.9 (MH⁺); HRMS Calcd. for C₂₂H₂₈CIN₂O₃(MH⁺): 403.1783.Found: 403.1780.

EXAMPLE 182(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-aceticacid

[0538] The title compound was prepared from[4-(4-oxo-piperidin-1-yl)-phenyl]-acetic acid (which was obtained inExample 149) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example179 as a pale yellowish solid; mp>140° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.25-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.60 (m, 7 H),2.88 (s, 3 H), 3.16 (s, 2 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 6.78 (d,J=8.2 Hz, 1 H), 6.84 (d, J=8.3 Hz, 2 H), 6.95 (dd, J=8.2, 1.7 Hz, 1 H),7.05 (d, J=8.3 Hz, 2 H), 7.16 (d, J=1.7 Hz, 1 H); MS (ES) m/z: 464.1(MH⁺); HRMS Calcd. for C₂₂H₂₈N₃O₆S(M−H)⁻: 462.1704. Found: 462.1696.

EXAMPLE 183(E)-3-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid ethyl ester

[0539] The title compound was prepared from(E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylic acid ethyl ester (whichwas obtained in Example 169) (0.27 g, 1.0 mmol) andN-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) (0.27 g, 1.1 mmol) according to theprocedure shown for Example 180 to give 0.40 g of yellow solid; m.p.103-106° C.; ¹H NMR (DMSO-d₆) δ1.24 (t, 3 H), 1.20-1.45 (m, 2 H),1.75-1.95 (m, 2 H), 2.55-2.95 (m, 5 H), 2.92 (t, 3 H), 3.67-3.85 (m, 2H), 4.14 (q, 2 H), 4.46-4.50 (m, 1 H), 6.34 (d, 1 H), 6.96 (d, 1 H),6.79-7.05 (m, 3 H), 7.05 (d, 1 H), 7.17 (d, 1 H), 7.56 (d, 2 H); MS (ES)m/z: 504.0 (MH⁺).

EXAMPLE 1843-(4-{4-[(R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-propionicacid

[0540] A solution of (E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylicacid (which was obtained in Example 170) (0.10 g, 0.40 mmol) andN-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methane-sulfonamide(which was obtained in Example 10) (0.12 g, 0.48 mmol) in methanol (15mL) was treated with avetic acid (0.03 g, 0.5 mmol), and 0.05 g of 10%Pd/C. The mixture was hydrogenated at 25 psi for 24 h, and then filteredthrough Celite and evaporated. The residue was triturated with ether togive 0.18 g of an off-white solid; m.p. 130-133° C.; ¹H NMR (DMSO-d₆)δ1.30-1.46 (m, 2 H), 1.84-1.95 (m, 2 H), 2.37-2.50 (m, 4 H), 2.60-2.78(m, 4 H), 2.92 (s, 3 H), 3.53-3.62 (m, 3 H), 4.46-4.55 (m, 1 H), 6.85(d, 2 H), 6.92-7.10 (m, 4 H), 7.18 (dd, 1 H); MS (ES) m/z: 478.3 (MH⁺).

EXAMPLE 185(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzyloxy)-aceticacid

[0541] A solution of[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-methanol(which wasobtained in Example 148)(3.49 g, 14 mmol) in tetrahydrofuran (100 mL)was treated with 60% sodium hydride in mineral oil (0.50, 21 mmol) andheated to a gentle reflux for 2 hours. After cooling to roomtemperature, iodoacetic acid sodium salt (2.91 g, 14 mmol) was added inone portion. The resulting mixture was heated to a gentle reflux foranother 2 hours. After cooling to room temperature the reaction wasquenched by careful addition of water and then partitioned between waterand methylene chloride. The aqueous layer was acidified by acetic acidand extracted with methylene chloride. The organic phase was dried oversodium sulfate, and concentrated. The residue was treated withconcentrated hydrochloric acid (150 mL) at room temperature. After 3hours the solution pH was adjusted to 4 by ˜28% ammonium hydroxide. Theaqueous layer was extracted with methylene chloride, and the combinedorganic phases were washed with water, dried over sodium sulfate andconcentrated to give a gum(0.95 g)[¹H NMR (300 MHz, CDCl₃) δ2.55 (t,J=6.1 Hz, 4 H), 3.61 (t, J=6.1 Hz, 4 H), 4.10 (s, 2 H), 4.56(s, 2 H),6.95 (d, J=8.6 Hz, 2 H), 7.29 (d, J=8.6 Hz, 2 H); MS (ES) m/z: 264.3(MH⁺)]. The gum (0.39 g) was dissolved in methanol (100 mL)/acetic acid(0.5 mL) and mixed withN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10)(0.25 g, 1 mmol). The resulting solution washydrogenated in the presence of 500 mg of 10% palladium on carbon underhydrogen:(5˜20 psi) for 4 hours. The catalyst was then removed byfiltering through a short pad of silica gel. The filtrate wasconcentrated and purified by silica gel chromatography(methanol/methylene chloride) to give the title compound as an off-whitesolid; mp>145° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.30-1.50 (m,2 H), 1.80-2.00 (m, 2 H), 2.60-2.80 (m, 5 H), 2.90 (s, 3 H), 3.50-3.70(m, 2 H), 3.65 (s, 2 H), 4.52 (s, 2 H), 4.54 (dd, J=8.3, 3.8 Hz, 1 H),6.75-6.90 (m, 3 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.02-7.20 (m, 3H); MS(ES) m/z: 494.2 (MH⁺); HRMS Calcd. for C₂₃H₃₀N₃O₇S(M−H)⁻: 492.1810.Found: 492.1804.

EXAMPLE 1864-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid

[0542] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example151) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 179 asa white solid; mp>85° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.60-3.00 (m, 5 H), 2.92 (s, 3H), 3.75-3.85 (m, 2 H), 4.53 (dd, J=8.3, 4.0 Hz, 1 H), 6.82 (d, J=8.3Hz, 1 H), 6.92 (d, J=8.9 Hz, 2 H), 7.01 (dd, J=8.3, 2.0 Hz, 1 H), 7.19(d, J=2.0 Hz, 1 H), 7.73 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 449.9 (MH⁺);HRMS Calcd. for C₂₁H₂₆N₃O₆S(M−H)⁻: 448.1549: Found: 448.1541.

EXAMPLE 187 3-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-propionicacid ethyl ester

[0543] To a solution of(E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesufonyl-amino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicethyl ester(which was obtained in Example 183) (0.12 g, 0.25 mmol) inethanol (2 mL) and tetrahydrofuran (1 mL) was added ammonium formate(0.16 g, 2.5 mmol), and 0.03 g of 10% Pd/C. The mixture was stirred atreflux for 18 hours. After cooling to room temperature, it was filteredthrough celite. The solvent was evaporated and the residue trituratedwith ether to give 0.11 g of a tan solid; m.p. 76-78° C.; ¹H NMR(DMSO-d₆) δ1.15 (t, 3 H), 1.20-1.40 (m, 2 H), 1.81-1.89 (m, 2 H),2.50-2.75 (m, 9 H), 2.91 (t, 3 H), 3.45-3.60 (m, 2 H), 4.03 (q, 2 H),4.46-4.50 (m, 1 H), 6.80-6.84 (m, 3 H), 6.98-7.04 (m, 3 H), 7.17 (d, 1H)); MS (ES) m/z: 506.0 (MH⁺).

EXAMPLE 1882-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-malonicacid diethyl ester

[0544] The title compound was prepared from2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethyl ester(which was obtained in Example 153) andN-[5-(-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 9) according to the procedure of Example 180 asa yellowish solid; mp>80° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.21 (t, J=7.0 Hz, 3 H), 1.23 (t, J=7.0 Hz, 3 H), 1.75-1.95 (m, 2 H),2.50-3.50 (m, 7 H), 2.92 (s, 3 H), 3.75-3.90 (m, 2 H), 4.21 (q, J=7.0Hz, 2 H), 4.31 (q, J=7.0 Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.81(d, J=8.2 Hz, 1 H), 6.94 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1 H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS(ES) m/z: 576.1 (MH⁺); HRMS Calcd. for C₂₈H₃₈N₃O₈S(MH⁺): 576.2374.Found: 576.2375.

EXAMPLE 1892-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-malonicacid monoethyl ester

[0545]2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzylidene)-malonicacid diethyl ester was prepared from2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethylester(which was obtained in Example 153) andN-[5-(-2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, J=7.0 Hz, 3 H),1.23 (t, J=7.0 Hz, 3 H), 1.75-1.95 (m, 2 H), 2.50-3.50 (m, 7 H), 2.90(s, 3 H), 3.75-3.90 (m, 2 H), 4.16 (q, J=7.0 Hz, 2 H), 4.29 (q, J=7.0Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.84 (d, J=8.2 Hz, 1 H), 6.94(d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 576.0 (MH⁺);HRMS Calcd. for C₂₈H₃₈N₃O₈S(MH⁺): 576.2374. Found: 576.2373.

[0546] The title compound was prepared by sodium hydroxide hydrolysis ofthe above diethyl ester as a pale grey solid; mp>170° C. (decomposed);.¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, J=7.0 Hz, 3 H), 1.40-1.60 (m, 2 H),1.90-2.05 (m, 2 H), 2.93 (s, 3 H), 2.70-4.00 (m, 7 H), 4.65-4.75 (m, 1H), 6.86 (d, J=8.1 Hz, 1 H), 6.93 (d, J=8.9 Hz, 2 H), 7.07 (dd, J=8.1,2.0 Hz, 1 H), 7.15-7.30 (m, 4 H); MS (ES) m/z: 547.9 (MH⁺); HRMS Calcd.for C₂₆H₃₄N₃O₈S(MH⁺): 548.2061. Found: 548.2057.

EXAMPLE 1904-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzamide

[0547] The title compound was prepared from4-(4-oxo-piperidin-1-yl)-benzamide(which was obtained in Example 147)andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamideExample 180 as a white solid; mp>75° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ1.2-1.40 (m, 2 H), 1.70-1.90 (m, 2 H), 2.55-2.95 (m, 5 H),2.97 (s, 3 H), 3.70-3.85 (m, 2 H), 4.48 (dd, J=8.0, 4.3 Hz, 1 H), 6.81(d, J=8.2 Hz, 1 H), 6.91 (d, J=9.0 Hz, 2 H), 6.99 (dd, J=8.2, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1 H), 7.67 (br s, 2 H), 7.72 (d, J=9.0 Hz, 2 H);MS (ES) m/z: 448.9 (MH⁺); HRMS Calcd. for C₂₁H₂₉N₄O₅S (MH⁺): 449.1853.Found: 449.1853.

EXAMPLE 191N-Benzyloxy-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl≡-benzamide

[0548] The title compound was prepared fromN-benzyloxy-4-(4-oxo-piperidin-1-yl)-benzamide(which was obtained inExample 155) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl[-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa white solid; mp>70° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.2-1.40 (m, 2 H), 1.70-1.90 (m, 2 H), 2.50-2.95 (m, 5 H), 2.92 (s, 3H), 3.70-3.85 (m, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H),4.89 (s, 2 H),6.81 (d, J=8.2 Hz, 1 H), 6.92 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0Hz, 1H), 7.18 (d, J=2.0 Hz, 1 H), 7.30-7.50 (m, 5 H), 7.60 (d, J=9.0 Hz,2 H); MS (ES) m/z: 555.3 (MH⁺); HRMS Calcd. for C₂₈H₃₅N₄O₆S (MH⁺):555.2272. Found: 555.2260.

EXAMPLE 192Diethyl(2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioate

[0549] The title compound was prepared from(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentaneodic acid diethylester (which was obtained in Example 157) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa white solid; mp>75° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.18(t, J=7.1 Hz, 3 H), 1.19 (t, J=7.1 Hz, 3 H), 1.20-1.45 (m, 2 H),1.80-2.10 (m, 4 H), 2.41 (t, J=7.4 Hz, 2 H), 2.50-2.95 (m, 5 H), 2.93(s, 3 H), 3.75-3.85 (m, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 4.10 (q, J=7.1Hz, 2 H), 4.35-4.45 (m, 1 H), 4.45-4.55 (m, 1 H), 6.82 (d, J=8.3 Hz, 1H), 6.94 (d, J=8.9 Hz, 2 H), 7.01 (dd, J=8.3, 2.0 Hz, 1 H), 7.18 (d,J=2.0 Hz, 1 H), 7.74 (d, J=8.9 Hz, 2 H), 8.38 (d, J=7.5 Hz, 1 H); MS(ES) m/z: 635.1 (MH⁺); HRMS Calcd. for C₃₀H₄₃N₄O₉S (MH⁺): 635.2745.Found: 635.2735.

EXAMPLE 193Ethyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}benzoyl)amino]propanoate.

[0550] The title compound was prepared from3-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-propionic acid ethyl ester(which was obtained in Example 158) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 179 asa white solid; mp>95° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.17(t, J=7.1 Hz, 3 H), 1.40-1.60 (m, 2 H), 1.90-2.10 (m, 2 H), 2.54 (t,J=7.0 Hz, 2 H), 2.70-2.95 (m, 5 H), 2.94 (s, 3 H), 3.35-3.50 (m, 2 H),3.80-3.95 (m, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 4.65-4.75 (m, 1 H), 6.88(d, J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 7.22 (d, J=1.9 Hz, 1 H), 7.69 (d, J=8.9 Hz, 2 H), 8.26 (t, J=5.2 Hz,1 H); MS (ES) m/z: 549.2 (MH⁺); HRMS Calcd. for C₂₆H₃₇N₄O₇S (MH⁺):549.2377. Found: 549.2369.

EXAMPLE 194(2S)-2-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioicacid

[0551] The title compound was prepared from(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanedioic aciddibenzyl ester (which was obtained in Example 156) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 179 asa white solid; mp>230° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.40-1.60 (m, 2 H), 1.90-2.10 (m, 4 H), 2.31 (t, J=7.5 Hz, 2 H),2.65-3.20 (m, 7 H), 3.00 (s, 3 H), 3.85-4.00 (m, 2 H), 4.25-4.35 (m, 1H), 4.65-4.80 (m, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.95 (d, J=8.7 Hz, 2H), 7.08 (dd, J=8.4, 1.2 Hz, 1 H), 7.25 (d, J=1.8 Hz, 1 H), 7.74 (d,J=8.7 Hz, 2 H), 8.14 (d, J=7.2 Hz, 1 H); MS (ES) m/z: 579.1 (MH⁺); HRMSCalcd. for C₂₆H₃₅N₄O₉S (MH⁺): 579.1973. Found: 579.1955.

EXAMPLE 195N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)-bete-alanine

[0552] The title compound was prepared from3-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-propionic acid benzyl ester(which was obtained in Example 159) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example179 as a white solid; mp>170° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.45 (m, 2 H), 1.80-1.95 (m, 2 H), 2.43 (t, J=7.0 Hz, 2 H),2.60-2.90 (m, 5 H), 2.90 (s, 3 H), 3.00-3.40 (m, 2 H), 3.70-3.85 (m, 2H), 4.50 (dd, J=8.0, 4.2 Hz, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.92 (d,J=8.9 Hz, 2 H), 7.01 (dd, J=8.3, 1.9 Hz, 1 H), 7.18 (d, J=1.9 Hz, 1 H),7.68 (d, J=8.9 Hz, 2 H), 8.26 (t, J=5.2 Hz, 1 H); MS (ES) m/z: 521.2(MH⁺); HRMS Calcd. for C₂₄H₃₃N₄O₇S (MH⁺): 521.2064. Found: 521.2056.

EXAMPLE 196Ethyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate

[0553] The title compound was prepared from ethyl{[4-(4-oxo-1-piperidinyl)benzoyl]amino}acetate(which was obtained inExample 161) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa white solid; mp>140° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ1.20(t, J=7.1 Hz, 3 H), 1.20-1.35 (m, 2 H), 1.75-1.90 (m, 2 H), 2.50-2.90(m, 5 H), 2.90 (s, 3 H), 3.70-3.85 (m, 2 H), 3.93 (d, J=5.8 Hz, 2 H),4.10 (q, J=7.1 Hz, 2 H), 4.47 (dd, J=7.9, 4.4 Hz, 1 H), 6.79 (d, J=8.3Hz,1 H), 6.90-7.00 (m, 3 H), 7.16 (d, J=2.0 Hz, 1 H), 7.72 (d, J=8.9 Hz,2 H), 8.58 (t, J=5.8 Hz, 1 H); MS (ES) m/z: 535.2 (MH⁺); HRMS Calcd. forC₂₆H₃₇N₄O₇S (MH⁺): 535.2221. Found: 535.2216.

EXAMPLE 197[(4-{4-[((2R)-2-Hydroxy-2-}4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]aceticacid

[0554] The title compound was prepared from ethyl[(4-{(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate(which was obtained in Example 196) by sodium hydroxide hydrolysis as awhite solid; mp>85° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.75-1.90 (m, 2 H), 2.55-2.90 (m, 5 H), 2.80 (s, 3H), 3.49 (d, J=4.5 Hz, 2 H), 3.70-3.80 (m, 2 H), 4.43 (dd, J=7.9, 4.4Hz, 1 H), 6.70 (d, J=7.4 Hz, 1 H), 6.81 (dd, J=7.4, 2.0 Hz, 1 H), 6.92(d, J=8.9 Hz, 2 H), 7.12 (d, J=2.0 Hz, 1 H), 7.54 (t, J=4.5 Hz, 1 H),7.64 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 507.2 (MH⁺); HRMS Calcd. forC₂₃H₃₁N₄O₇S (MH⁺): 507.1908. Found: 507.1912.

EXAMPLE 198(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid ethyl ester:

[0555] The title compound was prepared from ethyl4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzoylamino]-pentanoic acidethyl ester(which was obtained in Example 165) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asan off-white solid; mp>85° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ0.86 (d, J=6.3 Hz, 3 H), 0.92 (d, J=6.3 Hz, 3 H), 1.18 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2 H), 1.45-1.95 (m, 5 H), 2.55-2.92 (m, 5 H), 2.92 (s,3 H), 3.70-3.85 (m, 2 H), 4.10 (q, J=7.1 Hz, 2 H), 4.40-4.55 (m, 2 H),6.82 (d, J=8.3 Hz, 1 H), 6.94 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.3, 2.0Hz, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.75 (d, J=8.9 Hz, 2 H), 8.33 (d,J=7.7 Hz, 1 H); MS (ES) m/z: 591.3 (MH⁺); HRMS Calcd. for C₂₉H₄₃N₄O₇S(MH⁺): 591.2847. Found: 591.2840.

EXAMPLE 199(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid

[0556] The title compound was prepared from2-(4-(4-{2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid ethyl ester(which was obtained in Example 198) by sodium hydroxidehydrolysis as a white solid; mp>177° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ0.87 (d, J=6.3 Hz, 3 H), 0.90(d, J=6.3 Hz, 3 H), 1.35-1.75 (m,5 H), 1.90-2.00 (m, 2 H), 2.60-2.90 (m, 5 H), 2.94 (s, 3 H), 3.65-3.80(m, 2 H), 4.25-4.35 (m, 1 H), 4.60-4.65 (m, 1 H), 6.85 (d, J=8.3 Hz, 1H), 6.90 (d, J=8.9 Hz, 2 H), 7.05 (dd, J=8.3, 1.9 Hz, 1 H), 7.21 (d,J=1.9 Hz, 1 H), 7.73 (d, J=8.9 Hz, 2 H), 7.98 (d, J=7.7 Hz, 1 H); MS(ES)m/z: 561.3 (M−H)⁻; HRMS Calcd. for C₂₇H₃₇N₄O₇S (M−H)⁻: 561.2377. Found:561.2381.

EXAMPLE 2001-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid methyl ester

[0557] The title compound was prepared from1-[4-(4-oxo-piperidin-1-yl)-benzoyl]-pyrrolidine-(2S)-2-carboxylic acidmethyl ester(which was obtained in Example 160) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asan off-white solid; mp>80° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.75-1.95 (m, 4 H), 2.15-2.30 (m, 2 H), 2.50-2.90(m, 5 H), 2.90 (s, 3 H), 3.55-3.80 (m, 7 H), 4.40-4.55 (m, 2 H), 6.81(d, J=8.3 Hz, 1 H), 6.92 (d, J=8.7 Hz, 2 H), 6.98 (dd, J=8.3, 2.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1 H), 7.43 (d, J=8.7 Hz, 2 H); MS (ES) m/z: 561.3(MH⁺); HRMS Calcd. for C₂₇H₃₇N₄O₇S (MH⁺): 561.2377. Found: 561.2369.

EXAMPLE 2011-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid

[0558] The title compound was prepared from1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid methyl ester(which was obtained in Example 200) by sodium hydroxidehydrolysis as a white solid; mp>220° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆), δ1.20-1.40 (m, 2 H), 1.75-1.95 (m, 4 H), 2.50-2.90 (m, 7 H),2.62 (s, 3 H), 3.50-4.00 (m, 5 H), 4.35-4.45 (m, 1 H), 6.60 (d, J=8.3Hz, 1 H), 6.79 (d, J=8.7 Hz, 2 H), 6.90 (dd, J=8.2 Hz, 1 H), 7.06 (d,J=1.4 Hz, 1 H), 7.37 (d, J=8.6 Hz, 2 H); MS (ES) m/z: 545.6 (M−H)⁻; HRMSCalcd. for C₂₆H₃₃N₄O₇S (M−H)⁻: 545.2075. Found: 545.2064.

EXAMPLE 202(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid ethyl ester

[0559] The title compound was prepared from3-methyl-(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzyoylamino]-butyric acidethyl ester(which was obtained in in Example 163) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example180 as an off-white solid; mp>85° C. (decomposed); ¹H NMR (300 MHz,DMSO-d₆) δ0.92 (d, J=6.8 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 1.17 (t,J=7.1 Hz, 3 H), 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.05-2.20 (m, 1H), 2.55-2.90 (m, 5 H), 2.90 (s, 3 H), 3.70-3.85 (m, 2 H), 4.00-4.20 (m,2 H), 4.22 (t, J=7.7 Hz, 1 H), 4.48 (dd, J=8.0, 4.4 Hz, 1 H), 6.80 (d,J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 6.98 (dd, J=8.2, 2.0 Hz, 1 H),7.17 (d, J=2.0 Hz, 1 H), 7.76 (d, J=8.9 Hz, 2 H), 8.17 (d, J=7.9 Hz, 1H); MS (ES) m/z: 577.2 (MH⁺); HRMS Calcd. for C₂₉H₄₃N₄O₇S (MH⁺):577.2690. Found: 577.2682.

EXAMPLE 203(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid

[0560] The title compound was prepared from(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid ethyl ester(which was obtained in Example 202) by sodium hydroxidehydrolysis as a pale yellowish solid; mp>135° C. (decomposed); ¹H NMR(300 MHz, DMSO-d₆) δ0.90 (d, J=2.3 Hz, 3 H), 0.92 (d, J=2.3 Hz, 3 H),1.45-1.55 (m, 2 H), 1.90-2.05 (m, 2 H), 2.05-2.20 (m, 1 H), 2.60-2.94(m, 5 H), 2.94 (s, 3 H), 3.70-3.85 (m, 2 H), 4.11 (t, J=6.0 Hz, 1 H),4.65-4.75 (m, 1 H), 6.86 (d, J=8.3 Hz, 1 H), 6.91 (d, J=8.9 Hz, 2 H),7.06 (dd, J=8.3, 2.0 Hz, 1 H), 7.22 (d, J=2.0 Hz, 1 H), 7.65-7.75 (m, 3H); MS (ES) m/z: 549.3 (MH⁺); HRMS Calcd. for C₂₆H₃₅N₄O₇S (M−H)⁻:547.2231. Found: 547.2229.

EXAMPLE 204(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid methyl ester

[0561] The title compound was prepared from(2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-3-phenyl-propionic acidmethyl ester(which was obtained in Example 164) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asan off-white solid; mp>98° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.40 (m, 2 H), 1.80-1.90 (m, 2 H), 2.05-2.90 (m, 5 H), 2.91 (s, 3H), 3.00-3.20 (m, 2 H), 3.70-3.80 (m, 2 H), 4.47 (dd, J=8.0, 4.3 Hz, 1H), 4.50-4.65 (m, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.10-7.30 (m, 6 H), 7.67 (d, J=8.9Hz, 2 H), 8.47 (d, J=7.8 Hz, 1 H); MS (ES) m/z: 611.2 (MH⁺); HRMS Calcd.for C₃₁H₃₉N₄O₇S (MH⁺): 611.2534. Found: 611.2525.

EXAMPLE 205(2S)-2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid

[0562] The title compound was prepared from(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid methyl ester(which was obtained in Example 204) by sodium hydroxidehydrolysis as a pale yellowish solid; mp>160° C. (decomposed); ¹H NMR(300 MHz, DMSO-d₆) δ1.40-1.50 (m, 2 H), 1.90-2.05 (m, 2 H), 2.50-3.50(m, 7 H), 2.95 (s, 3 H), 3.69-3.75 (m, 2 H), 4.30-4.45 (m, 2 H),4.70-4.75 (m, 1 H), 6.83 (d, J=8.8 Hz, 2 H), 6.88 (d, J=8.3 Hz, 1 H),7.05-7.30 (m, 7 H), 7.63 (d, J=8.8 Hz, 2 H), 7.93 (br d, J=6.6 Hz, 1 H);MS (ES) m/z: 597.1 (MH⁺); HRMS Calcd. for C₃₀H₃₅N₄O₇S (M−H)⁻: 595.2231.Found: 595.2232.

EXAMPLE 206Methyl1-[(4-{4-[((2R)-2-hydroxy-2-}4-hydroxy-3-piperidinyl}benzoyl)amino]cyclopropanecarboxylate

[0563] The title compound was prepared from methyl1-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-cyclopropanecarboxylate (whichwas obtained in Example 167) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example180 as a white solid; mp>110° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.05-1.40 (m, 6 H), 1.75-1.90 (m, 2 H), 2.55-2.91 (m, 5 H), 2.91 (s, 3H), 3.58(s, 3 H), 3.69-3.80 (m, 2 H), 4.47 (dd, J=7.9, 4.4 Hz, 1 H),6.81 (d, J=8.5 Hz, 1 H), 6.85 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.5, 2.0Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.71 (d, J =8.9 Hz, 1 H), 8.72 (s, 1H); MS (ES) m/z: 547.1 (MH⁺); HRMS Calcd. for C₂₆H₃₅N₄O₇S (MH⁺):547.2221. Found: 547.2218.

EXAMPLE 207[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-amino]-aceticacid ethyl ester

[0564] A mixture of 4-(4-oxo-piperidin-1-yl)-benzoic acid (which wasobtained in Example 151)(0.30 g, 1.37 mmol),1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.53, 2.74mmol) and N-butylglycine ethyl ester (0.44 g, 2.7 mmol) was stirred inmethylene chloride (70 mL). N-methylmorpholine (0.28 g, 2.74 mol) wasadded dropwise and the mixture was stirred overnight. The mixture wasthen washed with 0.05 N hydrochloric acid and water. The resultingsolution was dried with magnesium sulfate and concentrated to give agum. The gum was dissolved in dimethylformamide (15 mL) and then treatedwithN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(0.25 g, 1 mmol) (which was obtained in Example 10), sodiumtriacetoxyborohydride (0.85 g, 4 mmol) and acetic acid (0.3 mL). Afterstirring at room temperature under a nitrogen atmosphere for 2 hours themixture was poured into a saturated aqueous sodium bicarbonate. Theaqueous layer was extracted with n-butanol and the concentrated gum waspurified by silica gel chromatography (methanol/methylene chloride) togive the title compound as a white solid; mp>60° C. (decomposed); ¹H NMR(300 MHz, DMSO-d₆) δ0.70-1.60 (m, 12 H), 1.75-1.95 (m, 2 H), 2.50-3.50(m, 7 H), 2.91 (s, 3 H), 3.60-3.75 (m, 2 H), 4.00-4.15 (m, 4 H), 4.47(dd, J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.5 Hz, 1 H), 6.90-7.00 (m, 3 H),7.05-7.25 (m, 3 H); MS (ES) m/z: 591.3 (MH⁺); HRMS Calcd. forC₂₉H₄₃N₄O₇S (MH⁺): 591.2847. Found: 591.2840.

EXAMPLE 208Methyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate

[0565] The title compound was prepared from methyl{[4-(4-oxo-1-piperidinyl)benzoyl]amino}acetate(which was obtained inExample 162) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa white solid; mp>75° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.35 (m, 2 H), 1.75-1.90 (m, 2 H), 2.50-2.90 (m, 5 H), 2.91 (s, 3H), 3.63 (s, 3 H), 3.70-3.85 (m, 2 H), 3.95(d, J=5.7 Hz, 2 H), 4.49 (dd,J=8.0, 4.3 Hz, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.96(d, J=8.9 Hz, 2 H),7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.71 (d, J=8.9Hz, 2 H), 8.60 (t, J=5.8 Hz, 1 H); MS (ES) m/z: 521.3 (MH⁺); HRMS Calcd.for C₂₅H₃₇N₄O₇S (M⁺): 520.2064. Found: 520.2054.

EXAMPLE 209(2S)-2-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid methyl ester

[0566] The title compound was prepared from methyl4-methyl-2-[(2S)-4-(4-oxo-piperidin-1-yl)-benzylamino]-pentanoic acidmethyl ester(which was obtained in Example 166) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) according to the procedure of Example 180 asa white solid; mp>90° C. (decomposed); ¹H NMR (300 MHz, DMSO-d₆) δ0.86(d, J=6.4 Hz, 3 H), 0.92 (d, J=6.4 Hz, 3 H), 1.20-1.40 (m, 2 H),1.50-1.95 (m, 5 H), 2.55-2.92 (m, 5 H), 2.91 (s, 3 H), 3.62 (s, 3 H),3.70-3.85 (m, 2 H), 4.40-4.55 (m, 2 H), 6.82 (d, J=8.2 Hz, 1 H), 6.93(d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 2 H), 7.18 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 2 H), 8.34 (d, J=7.7 Hz, 1 H); MS (ES) m/z: 577.3(MH⁺); HRMS Calcd. for C₂₈H₄₁N₄O₇S (MH⁺): 577.2690. Found: 577.2682.

EXAMPLE 210(2E)-3-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid

[0567] A solution of 0.10 g (0.2 mmol) of(E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid ethyl ester(which was obtained in Example 183) in ethanol (3 mL)was treated with 3 mL of 1 N NaOH. After 18 h at room temperature, themixture was acidified with acetic acid. The resulting suspension wasfiltered and the precipitate was washed with water, and dried in vacuoto give 0.09 g of a tan solid; m.p. 220° C.; ¹H NMR (DMSO-d₆) δ1.20-1.40(m, 2 H), 1.80-1.95 (m, 2 H), 2.57-2.95 (m, 5 H), 2.92 (t, 3 H),3.74-3.82 (m, 2 H), 4.48-4.52 (m, 1 H), 6.22 (s, 1 H), 6.27 (s, 1 H),6.81-7.03 (m, 4 H), 7.18 (d, 1 H), 7.42-7.49 (m, 3 H)); MS (ES) m/z:476.0 (MH⁺).

EXAMPLE 2114-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzamide

[0568] The title compound was prepared fromN-[(1S)-1-(hydroxymethyl)-3-methylbutyl]-4-(4-oxo-1-piperidinyl)benzamide(whichwas obtained in Example 173) (0.13 g, 0.4 mmol) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(0.12 g, 0.48 mmol) (which was obtained in Example 10)according to theprocedure shown for Example 180 to give 0.16 g of an off-white solid;m.p. 120-122 °C.; MS (ES) m/z: 549.3 (MH⁺); HRMS (ES) Calcd. forC₂₇H₄₁N₄O₆S (MH⁺); 549.2741, Found: 549.2735.

EXAMPLE 2124-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-sulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-l}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-oxoazepanyl]benzamide

[0569] The title compound was prepared fromN-[(3S)-2-oxoazepanyl]-4-(4-oxo-1-piperidinyl)benzamide (which wasobtained in Example 175) (0.13 g, 0.4 mmol) andN-[5-((1R)-2-amino-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) (0.12 g, 0.48 mmol) according to theprocedure shown for Example 180 to give 0.20 g of an off-white solid;m.p. 135-137° C.; MS (ES) m/z: 560.2 (MH⁺); HRMS (ES) Calcd. forC₂₇H₃₈N₅O₆S (MH⁺): 560.2537, Found: 560.2531.

EXAMPLE 213N-Butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)aminb]-1-piperidinyl}-N-(1H-tetraazol-5-ylmethyl)benzamide

[0570] The title compound was prepared fromN-butyl-4-(4-oxo-1-piperidinyl)-N-(1H-tetraazol-5-ylmethyl) benzamide(which was obtained in Example 178) (0.14 g, 0.4 mmol) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Example 10) (0.12 g, 0.48 mmol) according to theprocedure shown for Example 180 to give 0.22 g of an off-white solid;m.p. 168-170° C.; MS (ES) m/z: 587.5 (MH⁺); HRMS (ES) Calcd. forC₂₇H₃₉N₈O₅S (MH⁺): 587.2759, Found: 587.2751.

EXAMPLE 214 4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine

[0571] A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane(Synthesis, 606, 1981) (3.5 g, 13.3 mmol) and 10% Pd/C (0.5 g) in 100 mLof ethanol/methylene chloride(2:1) was pressurized with 30 psi hydrogenand shaken over 1 hours. The catalyst was then removed by filteringthrough a short pad of silica gel to give the title compound (2.8 g,90%) as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.85-2.00 (m, 4 H),3.00-3.10 (m, 4 H), 3.93 (s, 4 H), 6.60 (d, J=6.0 Hz, 2 H), 6.80 (d,J=6.0 Hz, 2 H); MS (ES) m/z: 235.2 (MH⁺); HRMS Calcd. for C₁₃H₁₈N₂O₂:234.1380. Found: 234.1371.

EXAMPLE 215N-{4-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide

[0572] To a stirred solution of4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine(which was obtained inExample 214) (2.8 g, 11.9 mol) in 1.4-dioxane (150 mL) and triethylamine(7 mL) was added a solution of N-acetylsulfanilyl chloride (3.5 g, 15mmol) in 75 mL of 1,4-dioxane at room temperature. The reaction wasstirred for 18 hours. The reaction mixture was concentrated. The residuewas dissolved in methylene chloride and washed with diluted hydrochloricacid. The white solid in water layer was collected and dried to give thetitle compound as a white solid (2.5 g, 43%); ¹H NMR (300 MHz, DMSO-d₆)δ1.92 (brs, 4 H), 2.06 (s, 3 H), 3.68 (brs, 4 H), 3.93 (s, 4 H), 7.06(d, J=8.4 Hz, 2 H), 7.33 (brs, 2 H), 7.68 (d, J=9.0 Hz, 2 H), 7.71 (d,J=9.0Hz, 2 H), 10.24 (brs, 1 H), 10.38 (s, 1 H); MS (ES) m/z: 432.3(MH⁺); HRMS Calcd. for C₂₁H₂₅N₃O₅S(M⁺): 431.1515. Found: 431.1530.

EXAMPLE 216N-{4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide

[0573]N-{4-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide(which was obtained in Example 215) (2.2 g, 5.1 mmol) was treated withconcentrated hydrochloric acid (50 mL) at 0° C. and then allowed to warmto room temperature. After 30 min., ˜20 mL of 5 N NaOH was addeddropwise and the precipitate was collected by filtration, and dried overP₂O₅ to give the title compound as a white solid (1.2 g); ¹H NMR (300MHz, DMSO-d₆) δ2.06 (s, 3 H), 2.43 (t, J=5.8 Hz, 4 H), 3.53 (t, J=5.8Hz, 4 H), 6.85-7.05 (m, 4 H), 7.62 (d, J=9.0 Hz, 2 H), 7.71 (d, J=9.0Hz, 2 H), 9.81 (s, 1 H), 10.35 (s, 1 H); MS (ES) m/z: 388.3 (MH⁺); HRMSCalcd. for C₁₉H₂₁N₃O₄S(M⁺):387.1253. Found: 387.1272.

EXAMPLE 217N-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-4-methoxy-benzenesulfonamide

[0574] The title compound was prepared from4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtainedin Example 214) and 4-methoxybenzenesulfonyl chloride according to theprocedure of Example 215 as a crystalline solid; ¹H NMR (300 MHz,DMSO-d₆) δ1.65 (t, J=5.6 Hz, 4 H), 3.15 (t, J=5.6 Hz, 4 H), 3.79 (s, 3H), 3.88 (s, 4 H), 6.69 (d, J=9.0 Hz, 2 H), 9.63 (s, 1 H); MS (ES) m/z:405.3 (MH⁺); HRMS Calcd. for C₂₀H₂₄N₂O₅S(M⁺): 404.1406. Found: 404.1402.Anal. Calcd. for C₂₀H₂₄N₂O₅S: C, 59.39; H, 5.98; N, 6.93. Found: C,59.48; H, 6.03; N, 6.85.

EXAMPLE 2184-Methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]benzenesulfonamide

[0575] The title compound was prepared fromN-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-4-methoxy-benzenesulfonamide(which was obtained in Example 217) according to the procedure ofExample 216 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.37 (t, J=6.0Hz, 4 H), 3.50 (t, J=6.0 Hz, 4 H), 3.79 (s, 3 H), 6.88 (d, J=9.0 Hz, 2H), 6.93 (d, J=9.0 Hz, 2 H), 7.01 (d, J=9.0 Hz, 2 H), 7.60 (d, J=9.0 Hz,2 H), 9.66 (s, 1 H); MS (ES) m/z: 361.2 (MH⁺); HRMS Calcd. forC₁₈H₂₀N₂O₄S(M⁺): 360.1144. Found: 360.1146.

EXAMPLE 219 8-(2-Nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane

[0576] A solution of 2-fluoronitrobenzene (10 g, 70.9 mmol) and1,4-dioxa-8-aza-spiro [4.5]decane (10 g, 69.8 mmol) in pyridine (70 mL)was heated at 70° C. for 1 day, diluted with water, and extracted withethyl acetate. The combined organic extracts were washed with brine,dried with sodium sulfate, and filtered. The solvent was removed underreduced pressure to give the title compound (15 g) as a red oil; ¹H NMR(300 MHz, CDCl₃) δ1.88 (t, J=5.6 Hz, 4 H), 3.16 (t, J=5.6 Hz, 4 H), 4.00(s, 4 H), 7.03 (dd, J=8.2, 8.2 Hz, 2 H), 7.17 (d, J=8.2 Hz, 2 H), 7.40(ddd, J=8.2, 8.2, 1.7 Hz, 1 H), 7.77(dd, J=8.4, 1.7Hz, 1 H); MS (ES)m/z: 265.1 (MH⁺); HRMS Calcd. for C₁₃H₁₇N₂O₄(MH⁺): 265.1188. Found:265.1164.

EXAMPLE 220 2-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylaminehydrochloride

[0577] A mixture of8-(2-nitro-phenyl)-1,4-dioxa-8-aza-spiro[5.5]decane(which was obtainedin Example 219) (14.1 g, 15.9 mmol) and 10% Pd/C (1 g) in 100 mL ofethanol was pressurized with 30 psi hydrogen and shaken over 2 hours.The catalyst was then removed by filtering through a short pad of silicagel. Hydrogen chloride (1.0 M solution in diethyl ether) was added andthe solid that formed was collected by filtration to give the titlecompound as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.85-2.00 (m, 4H), 3.00-3.40 (m, 4 H), 3.93 (s, 4 H), 7.12-7.28 (m, 2 H), 7.28-7.55 (m,2 H); MS (ES) m/z: 235.2 (MH⁺); HRMS Calcd. for C₁₃H₁₉N₂O₂(MH⁺):235.1447. Found: 235.1451.

EXAMPLE 221N-{4-[2-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide

[0578] The title compound was prepared from2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine hydrochloride (whichwas obtained in Example 220) and N-acetylsulfanilyl chloride accordingto the procedure of Example 215 as a crystalline solid; ¹H NMR (300 MHz,DMSO-d₆) δ1.73 (t, J=5.4 Hz, 4 H), 2.73 (t, J=5.4 Hz, 4 H), 3.33 (s, 4H), 3.89 (s, 3 H), 7.00-7.10 (m, 2 H), 7.10-7.20 (m, 1 H), 7.30-7.40 (m,1 H), 7.67 (d, J=9.3 Hz, 2 H), 7.71 (d, J=9.3 Hz, 2 H), 8.79 (s, 1 H),10.29 (s, 1 H); MS (ES) m/z: 432.2 (MH⁺); HRMS Calcd. for C₂₁H₂₆N₃O₅S(MH⁺): 432.1593. Found: 432.1597. Anal. Calcd. for C₂₁N₂₅N₃O₅S: C,58.45; H, 5.84; N, 9.74. Found: C, 58.41; H, 5.83; N, 9.72.

EXAMPLE 222N-{4-[2-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide

[0579] The title compound was prepared fromN-{4-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfamoyl]-phenyl}-acetamide(which was obtained in Example 221) according to the procedure ofExample 216 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.05 (s, 3 H),2.43 (t, J=5.9 Hz, 4 H), 2.77 (t, J=5.9 Hz, 4 H), 7.00-7.20 (m, 3 H),7.35-7.45 (m, 3 H), 7.35-7.45 (m, 1 H), 7.64 (d, J=6.9 Hz, 2 H), 7.71(d, J=6.9 Hz, 2 H), 9.10 (s, 1 H), 10.30 (s, 1 H); MS (ES) m/z: 388.3(MH⁺); HRMS Calcd. for C₁₉H₂₂N₃O₄S (MH⁺): 388.1331. Found: 388.1341.

EXAMPLE 223N-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-4-(3-hexyl-ureido)-benzenesulfonamide

[0580] The title compound was prepared from4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (which was obtainedin Example 214) and 4-(3-hexyl-ureido)benzenesulfonyl chloride (U.S.Pat. No. 5,561,142/1996) according to the procedure of Example 215 as awhite flake; ¹H NMR (300 MHz, DMSO-d₆) 0.86 (t, J=6.5 Hz, 3 H),1.20-1.50 (m, 8 H), 1.65 (t, J=5.7 Hz, 4 H), 3.00-3.10 (m, 2 H), 3.14(t, J=5.7 Hz, 4 H), 3.88 (s, 4 H), 6.28 (t, J=5.6 Hz, 1 H), 6.79 (d,J=9.0 Hz, 2 H), 6.87 (d, J=9.0 Hz, 2 H), 7.45 (d, J=9.1 Hz, 2 H), 7.51(d, J=9.1 Hz, 2 H), 8.82 (s, 1 H); MS (ES) m/z: 517.2 (MH⁺); HRMS Calcd.for C₂₆H₃₇N₄O₅S (MH⁺): 517.2485. Found: 517.2377. Anal. Calcd. forC₂₆H₃₆N₄O₅S: C, 60.44; H, 7.02; N, 10.84. Found: C, 60.29; H, 6.95; N,10.91.

EXAMPLE 224 1-(4-Amino-phenyl)-piperidin-4-one hydrochloride

[0581] A mixture of 1-(4-nitro-phenyl)-piperidin-4-one (Synthesis 1981,606) (4.0 g, 18 mmol) and 500 mg of 10% Pd/C in 75 mL of methylenechloride was hydrogenated under H₂ (5˜10 psi) for 1 hour. The catalystwas then removed by filtering through a short pad of silica gel. Thefiltrate was treated with hydrogen chloride gas and the precipitate wascollected to give 2 g of the title compound as a tan solid; ¹H NMR (300MHz, DMSO-d₆) δ2.44 (t, J=6.0 Hz, 4 H), 3.65 (t, J=6.0 Hz, 4 H), 7.14(d, J=9.0 Hz, 2 H), 7.25 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 190.9 (MH ⁺);HRMS Calcd. for C₁₁H₁₅N₂O (MH⁺): 190.1106. Found: 190.1096.

EXAMPLE 2254-(3-Hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]benzenesulfonamide

[0582] Method A: The title compound was prepared fromN-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-4-(3-hexyl-ureido)-benzenesulfonamide(which was obtained in Example 223) according to the procedure ofExample 216 a as a grey solid.

[0583] Method B: To a stirred solution of1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained inExample 224) (3.95 g, 15 mmol) in 250 mL of dioxane was added 13.7 mL oftriethylamine followed by 4-(3-hexyl-ureido)benzenesulfonyl chloride(U.S. Pat. No. 5,561,142/1996)(6.36 g, 20 mmol). After being stirredover 1 day, the mixture was concentrated and the residue chromatographedon silica gel (0 to 10% methanol/methylene chloride) to afford 3.0 g ofthe title compound; ¹H NMR (300 MHz, CDCl₃) δ0.88 (t, J=7.0 Hz, 3 H),1.20-1.60 (m, 8 H), 2.45-2.60 (m, 4 H), 3.20-3.75 (m, 2 H), 3.50-3.60(m, 4 H), 4.90 (brs, 1 H), 6.50 (brs, 1 H), 6.82 (d, J=8.5 Hz, 2 H),6.97 (d, J=8.5 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.56 (d, J=8.7 Hz, 2H); MS (ES) m/z: 473.5 (MH⁺); HRMS Calcd. for C₂₄H₂₅N₄O₄S (MH⁺):473.2233. Found: 473.2220.

EXAMPLE 2264-[4-(3-Cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-yl])-N-[4-(4-oxo-piperidin-1-yl)-phenyl]benzenesulfonamide

[0584] The title compound was prepared from1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example 224)and4-[(3-cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-phenylsulfonylchloride (U.S. Pat. No. 5,561,142/1996) according to the Method B ofExample 225 as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.90-1.80(m, 17 H), 2.36 (t, J=6.0 Hz, 2 H), 3.49 (t, J=6.0 Hz, 2 H), 3.96 (t,J=7.0 Hz, 2 H), 6.86 (d, J=6.7 Hz, 2 H), 6.94 (d, J=6.7 Hz, 2 H), 7.86(d, J=8.8 Hz, 2 H), 8.06 (d, J=8.8 Hz, 2 H), 9.92 (s, 1 H); MS (ES) m/z:525.1 (MH⁺); HRMS Calcd. for C₂₆H₃₂N₆O₄S (M⁺): 524.2205. Found:524.2193. Anal. Calcd. for C₂₆H₃₂N₆O₄S: C, 59.52; H, 6.15; N, 16.02.Found: C, 59.50; H, 6.28; N, 15.81.

EXAMPLE 227 5-Pyridin-2-yl-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0585] The title compound was prepared from5-pyridin-2-yl-thiophene-2-sulphonyl chloride and1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example 224)according to the procedure B of Example 225 as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ2.37 (t, J=6.0 Hz, 4 H), 3.52 (t, J=6.0 Hz, 4 H),6.89 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.39 (dd, J =4.2, 1.5Hz, 1 H), 7.42 (d, J=2.1 Hz, 1 H), 7.76 (d, J=2.1 Hz, 1 H), 7.90 (dd,J=7.8, 1.5 Hz, 1 H), 8.00 (d, J=7.8 Hz, 1 H), 8.53 (d, J=4.2 Hz, 1 H),10.05 (s, 1 H); MS (ES) m/z: 413.9 (MH⁺); HRMS Calcd. forC₂₀H₁₉N₃O₃S₂(M⁺): 413.0867. Found: 413.0877.

EXAMPLE 228 Butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0586] The title compound was prepared from 1-butanesulfonyl chlorideand 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtainedin Example 224) according to the procedure B of Example 225 as acrystalline solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.83 (t, J=7.3 Hz, 3 H),1.25-1.40 (m, 2 H), 1.55-1.70 (m, 2 H), 2.40 (t, J=5.9 Hz, 4 H), 2.94(t, J=7.6 Hz, 2 H), 3.54 (t, J=5.9 Hz, 4 H), 7.00 (d, J=9.0 Hz, 2 H),7.09 (d, J=9.0 Hz, 2 H), 9.34 (s, 1 H); MS (ES) m/z: 311.0 (MH⁺); HRMSCalcd. for C₁₅H₂₂N₂O₂S(M⁺): 310.1351. Found: 310.1375. Anal. Calcd. forC₁₅H₂₂N₂O₂S: C, 58.04; H, 7.14; N, 9.02. Found: C, 57.78; H, 6.95; N,8.83.

EXAMPLE 2295-(5-Trifluoromethyl-pyridin-2-sulfonyl)-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0587] The title compound was prepared from5-(5-trifluoromethyl-pyridin-2-sulfonyl)-thiophene-2-sulphonyl chlorideand 1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example224) according to the procedure B of Example 225 as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ2.37 (t, J=4.5 Hz, 4 H), 3.52 (t, J=4.5 Hz, 4H), 6.90-7.10 (m, 4 H), 7.90 (d, J=1.2 Hz, 1 H), 8.41 (d, J=6.3 Hz, 1H), 8.50 (d, J=1.2 Hz, 1 H), 8.62 (dd, J=6.3, 1.5 Hz, 1 H), 9.23 (s, 1H), 9.89 (s, 1 H); MS (ES) m/z: 545.9 (MH⁺); HRMS Calcd. forC₂₁H₁₉F₃N₃O₅S₃(MH⁺): 546.0439. Found: 546.0466. Anal. Calcd. forC₂₁H₁₈F₃N₃O₅S₃: C, 46.23; H, 3.33; N, 7.70. Found: C, 46.46; H, 3.39; N,7.35.

EXAMPLE 230 Octane-1-sulfonic acid[4-(4-oxo-1-piperidinyl)-phenyl]-amide

[0588] The title compound was prepared from 1-octanesulfonyl chlorideand 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtainedin Example 224) according to the procedure B of Example 225 as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ0.84 (t, J=5.4 Hz, 3 H), 1.15-1.40 (m,10 H), 1.60-1.75 (m, 2 H), 2.40 (t, J=4.5 Hz, 4 H), 2.94 (t, J=5.7 Hz, 2H), 3.54 (t, J=4.5 Hz, 4 H), 6.99 (d, J=6.9 Hz, 2 H), 7.09 (d, J=6.9 Hz,2 H), 9.31 (s, 1 H); MS (ES) m/z: 367.0 (MH⁺); HRMS Calcd. forC₁₉H₃₀N₂O₂S(M⁺): 366.1977. Found: 366.1969. Anal. Calcd. forC₁₉H₃₀N₂O₂S: C, 62.26; H, 8.25; N, 7.64. Found: C, 62.40; H, 7.98; N,7.59.

EXAMPLE 2314-(2,4-Dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0589] The title compound was prepared from4-(2,4-dioxo-thiazolidin-5-ylmethyl) benzenesulfonylchloride (J. Med.Chem. 1992, 35, 1853) and 1-(4-amino-phenyl)-piperidin-4-onehydrochloride (which was obtained in Example 224) according to theprocedure B of Example 225 as a yellowish solid; ¹H NMR (300 MHz,DMSO-d₆) δ2.37 (t, J=6.0 Hz, 4 H), 3.10-3.60 (m, 2 H), 3.44 (t, J=6.0Hz, 4 H), 4.95 (dd, J=12.3, 6.0 Hz, 1 H), 6.80-7.00 (m, 4 H), 7.27 (d,J=8.1 Hz, 2 H), 7.63 (d, J=8.1 Hz, 2 H), 9.77 (brs, 1 H), 12.09 (brs, 1H); MS (ES) m/z: 459.9 (MH⁺); HRMS Calcd. for C₂₁H₂₁N₃O₅S₂ M⁺):459.0923. Found: 459.0930.

EXAMPLE 232{4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acidmethyl ester

[0590] The title compound was prepared from(4-chlorosulfonyl-phenoxy)-acetic acid methyl ester (Chem. Pharm. Bull.1995, 43, 1132) and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride(which was obtained in Example 224) according to the procedure B ofExample 225 as a grey solid; MS (ES) m/z: 418.9 (MH⁺); HRMS Calcd. forC₂₀H₂₃N₂O₆S(MH⁺): 419.1271. Found: 419.1271.

EXAMPLE 233 4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid

[0591] The title compound was prepared from 4-(chlorosulfonyl) benzoicacid and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which wasobtained in Example 224) according to the procedure B of Example 225 asa pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.36 (t, J=6.0 Hz, 4 H),3.49 (t, J=6.0 Hz, 4 H), 6.87 (d, J=9.3 Hz, 2 H), 6.91 (d, J=9.3 Hz, 2H), 7.77 (d, J=8.1 Hz, 2 H), 8.04 (d, J=8.1 Hz, 2 H), 9.97 (s, 1 H),13.10 (brs, 1 H); MS (ES) m/z: 374.9 (MH⁺); HRMS Calcd. forC₁₈H₁₉N₂O₅S(MH⁺): 375.1009. Found: 375.1009.

EXAMPLE 2343-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-thiophene-2-carboxylic acidmethyl ester

[0592] The title compound was prepared from2-(methoxycarbonyl)thiophene-3-sulphonyl chloride and1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained inExample 224) according to the procedure B of Example 225 as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ2.37 (t, J=6.0 Hz, 4 H), 3.50 (t,J=6.0 Hz, 4 H), 3.89 (s, 3 H), 6.90 (d, J=9.1 Hz, 2 H), 6.96 (d, J=9.1Hz, 2 H), 7.33 (d, J=6.9 Hz, 1 H), 7.90 (d, J=6.9 Hz, 1 H), 9.50 (s, 1H); MS (ES) m/z: 395.0 (MH⁺); HRMS Calcd. for C₁₇H₁₉N₂O₅S₂(MH⁺):395.0736. Found: 395.0721.

EXAMPLE 235 4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acidethyl ester

[0593] A stirred solution of4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid (which wasobtained in Example 234) (1.4 g, 3.74 mmol) in 50 mL of ethanol wastreated with hydrochloride gas at room temperature. After four hours thesolution was concentrated and the residue was dissolved in concentratedhydrochloric acid (200 mL) at room temperature. After another 3 hoursthe pH was adjusted to ˜5 and the precipitate was collected byfiltration, and dried over P₂O₅ to give the title compound as ayellowish solid (1.1 g, 70%); ¹H NMR (300 MHz, CDCl₃) δ1.40 (t, J=7.1Hz, 3 H), 2.36 (t, J=6.0 Hz, 4 H), 3.56 (t, J=6.0 Hz, 4 H), 4.41 (q,J=7.1 Hz, 2 H), 6.82 (d, J=8.9 Hz, 2 H), 6.97 (d, J=8.9 Hz, 2 H), 7.78(d, J=8.3 Hz, 2 H), 8.07 (d, J=8.3 Hz, 2 H); MS (ES) m/z: 403.2 (MH⁺);HRMS Calcd. for C₂₀H₂₃N₂O₅S(MH⁺): 403.1328. Found: 403.1330.

EXAMPLE 236 [4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic acidbenzyl ester

[0594] The title compound was prepared frombenzyloxycarbonylmethylsulfonylchloride (J. Antibiot., 1994, 47, 1041)and 1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example224) according to the procedure B of Example 225 as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ2.42 (t, J=6.0 Hz, 4 H), 3.55 (t, J=6.0 Hz, 4H), 4.16 (s, 2 H), 5.16 (s, 2 H), 6.99 (d, J=9.0 Hz, 2 H), 7.10 (d,J=9.0 Hz, 2 H), 9.73 (s, 1 H); MS (ES) m/z: 403.2 (MH⁺); HRMS Calcd. forC₂₀H₂₂N₂O₅S(M⁺): 402.1250. Found: 402.1237.

EXAMPLE 237 Pyridine-3-sulfonic acid[4-(4-oxopiperidin-1-yl)-phenyl]amide

[0595] To a stirred solution of 1-(4-amino-phenyl)-piperidin-4-onehydrochloride (which was obtained in Example 224) (8.76 g, 0.32 mol) inmethylene chloride (100 mL) at room temperature was added triethylamine(9 mL). To this mixture was added a mixture of 3-pyridinesulfonylchloride (7.45 g, 0.035 mol) and triethylamine (9 mL). The reaction wasstirred for 18 hours. The reaction mixture was concentrated. The productwas flash silica gel chromatographed eluting with 7:3 ethylacetate/hexanes and then flash silica gel chromatographed eluting with3% methanol in methylene chloride to give the titled compound as ayellow solid (1.34 g, 13%); ¹H NMR (300 MHz, CDCl₃) δ2.54(t, J=6 Hz, 4H), 3.56(t, J=6 Hz, 4 H), 6.79(s, 1 H), 6.85(d, J=12 Hz, 2 H), 6.98(d,J=12 Hz, 2 H), 7.40(m, 1H), 7.97(dd, J=3 Hz, 1 H), 8.75(dd, J=6 Hz, 1H), 8.90(d, J=3 Hz, 1 H); MS (ES) m/z: 331.9 (MH⁺, 100%); HRMS Calcd.for C₁₆H₁₇N₃O₃S(MH⁺): 332.1063. Found: 332.1063.

EXAMPLE 238 5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0596] The title compound was prepared according to the procedure ofExample 225 as a light yellow solid; ¹H NMR (300 MHz, CDCl₃) δ2.53 (t,J=6.06 Hz, 4H), 2.81 (s, 3H), 3.56 (t, J=6.06 Hz, 4H), 6.39 (s, 1H),6.82 (d, 1H), 7.02 (d, 1H), 7.57 (dd, J=2.01 Hz, 8.07 Hz, 1H), 7.70-7.71(m, 1H), 7.80 (s, 1H), 7.83 (s, 1H), 7.90 (d, J=2.16 Hz, 1H); MS (ES)m/z: 434.8 (MH⁺).

EXAMPLE 2394-Cyano-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0597] The title compound was prepared according to the procedure ofExample 225 as a yellow solid; ¹H NMR (300 MHz, CDCl₃) δ2.56 (t, J=6.09Hz, 2H), 3.58 (t, J=6.03 Hz, 2H), 6.42 (s, 1H), 6.80-6.88 (m, 2H),6.93-6.98 (m, 2H), 7.69-7.75 (m, 1H), 7.79-7.89 (m, 2H), 8.06-8.10(m,1H); MS (ES) m/z: 355.9 (MH⁺).

EXAMPLE 240 3-Bromo-5-chloro-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0598] The title compound was prepared according to the procedure ofExample 225 as an olive-green foam; ¹H NMR (300 MHz, CDCl₃) δ2.54 (t,J=6.06 Hz, 4H), 3.60 (t, J=6.03 Hz, 4H), 6.79 (s, 1H), 6.83-6.91 (m,2H), 6.92-6.95 (m, 1H), 7.07-7.11 (m, 1H), 7.21-7.24 (m, 1H).

EXAMPLE 241 5-Isoxazol-3-yl-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide

[0599] The title compound was prepared according to the procedure ofExample 225 as a yellow/brown solid; ¹H NMR (300 MHz, CDCl₃) δ2.55 (t,J=6.12 Hz, 4H), 3.58 (t, J=6.00 Hz, 4H), 6.46-6.49 (m, 2H), 6.86-6.91(m, 2H), 7.02-7.09 (m, 2H), 7.12 (s, 1H), 7.36-7.41 (m, 2H); MS (ES)m/z: 403.9 (MH⁺).

EXAMPLE 2423,4-Dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0600] The title compound was prepared according to the procedure ofExample 225 as a dull yellow solid; ¹H NMR (300 MHz, CDCl₃) δ2.54 (t,J=4.5 Hz, 4H), 3.55 (t, J=4.5 Hz, 4H), 3.83 (s, 3H), 3.91 (s, 3H), 6.21(brs, 1H), 6.83-6.87 (m, 3H), 6.94-7.03 (m, 2H), 7.12 (d, J=1.5 Hz, 2H);MS (ES) m/z: 391.0 (MH⁺); HRMS found for C₁₈H₁₇N₃O₄S₂: 391.1333.

EXAMPLE 2433,4-Dichloro-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0601] To a stirred solution of 0.5 g (1.9 mmol) of the hydrochloridesalt of 1-(4-amino-phenyl)-piperidin-4-one (which was obtained inExample 224) in 10 mL of anhydrous methylene chloride was added 0.99 mL(5.7 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 0.51g (2.1 mmol) of 3,4-dichlorobenzene sulfonyl chloride was added and themixture was allowed to stir overnight. The reaction mixture was quenchedwith water and the solvent was removed in vacuo. The residue wasdissolved in ethyl acetate and washed twice with water, twice withbrine, dried over sodium sulfate and then concentrated in vacuo. Theresidue was then purified by flash chromatography (10% EtOAc in hexanesto 50% EtOAc in hexanes) and the title compound was collected as 0.25 gof a yellow solid; ¹H NMR (300 MHz, CDCl₃) δ2.55 (t, J=6.09 Hz, 4H),3.58 (t, J=6.03 Hz, 4H), 6.33 (s, 1H), 6.60-6.88 (m, 2H), 6.95-7.00 (m,2H), 7.50 (d, J=1.47 Hz, 2H), 7.78-7.79 (m, 1H); MS (ES) m/z: 398.8(MH⁺); HRMS found for C₁₇H₁₆Cl₂N₂O₃S: 398.0227.

EXAMPLE 244N-[4-(4-Oxo-piperidin-1-yl)-phenyl]-4-trifluoromethyl-benzenesulfonamide

[0602] The title compound was prepared from 4-(trifluoromethyl)benzenesulfonyl chloride according to the procedure of Example 243 as a yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.55 (t, J=6.12 Hz, 4H), 3.57 (t, J=6.0Hz, 4H), 6.41 (s, 1H), 6.81-6.89 (m, 2H), 6.95-7.00 (m, 2H), 7.71 (d,J=8.37 Hz, 2H), 7.83 (d, J=8.31 Hz, 2H), MS (ES) m/z: 398.9 (MH⁺); HRMSfound for C₁₈H₁₇F₃N₂O₃S: 398.0910.

EXAMPLE 245N-[4-(4-Oxo-piperidin-1-yl)-phenyl]-4-trifluoromethoxy-benzenesulfonamide

[0603] The title compound was prepared from 4-(trifluoromethoxy)benzenesulfonyl chloride according to the procedure of Example 243 as a yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.54 (t, J=6.06 Hz, 4H), 3.56 (t, J=6.03Hz, 4H), 6.45 (s, 1H), 6.81-6.89 (m, 2H), 6.95-7.00 (m, 2H), 7.24-7.27(m, 2H), 7.74-7.79 (m, 2H); MS (ES) m/z: 414.9 (MH⁺); HRMS found forC₁₈H₁₇F₃N₂O₄S: 414.0854.

EXAMPLE 2464-Chloro-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0604] The title compound was prepared from 4-chlorobenzene sulfonylchloride according to the procedure of Example 243 as a yellow solid; ¹HNMR (300 MHz, CDCl₃) δ2.54 (t, J=6.09 Hz, 4H), 3.56 (t, J=6.03 Hz, 4H),6.51 (s, 1H), 6.80-6.88 (m, 2H), 6.94-7.00 (m, 2H), 7.38-7.43 (m, 2H),7.61-7.67 (m, 2H); MS (ES) m/z: 364.9 (MH⁺); HRMS found forC₁₇H₁₇ClN₂O₃S: 364.0652.

EXAMPLE 2474-Butyl-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0605] The title compound was prepared from 4-n-butylbenzene sulfonylchloride according to the procedure of Example 243 as a light greysolid; ¹H NMR (300 MHz, CDCl₃) δ0.91 (t, J=7.26 Hz, 3H), 1.23-1.39 (m,2H), 1.53-1.64 (m, 2H), 2.53 (t, J=6.12 Hz, 4H), 2.64 (t, J=7.62 Hz,2H), 3.55 (t, J=6.0 Hz, 4H), 6.21 (s, 1H), 6.80-6.85 (m, 2H), 6.94-6.99(m, 2H), 7.21-7.24 (m, 2H), 7.59-7.62 (m, 2H); HRMS found forC₂₁H₂₆N₂O₃S: 386.1660.

EXAMPLE 2482,5-Dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0606] The title compound was prepared from 2,5-dimethoxybenzenesulfonyl chloride according to the procedure of Example 243 as a yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.63 (t, J=6.15 Hz, 4H), 3.72 (s, 3H),3.82 (t, J=6.15 Hz, 4H), 4.03 (s, 3H), 6.77-6.91 (m, 2H), 6.96-7.02 (m,2H), 7.27-7.32 (m, 2H), 8.13-8.21 (m, 2H); MS (ES) m/z: 391.0 (MH⁺);HRMS found for C₁₉H₂₂N₂O₅S: 390.9799.

EXAMPLE 2493,5-Dichloro-N-[4-(4-oxo-piperidin-yl)-phenyl]-benzenesulfonamide

[0607] The title compound was prepared from 3,5-dichlorobenzene sulfonylchloride according to the procedure of Example 243 as a pale yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.5 (t, 4H), 3.55 (t, 4H), 6.41 (s, 1H),6.84-6.91 (m, 2H), 6.96-7.02 (m, 2H), 7.52 (t, J=1.86 Hz, 1H), 7.56 (d,J=1.86 Hz, 2H); MS (ES) m/z: 398.8 (MH⁺); HRMS found for C₁₇H₁₆Cl₂N₂O₃S:398.1622.

EXAMPLE 2505-Bromo-2-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide

[0608] The title compound was prepared from 5-bromo-2-methoxybenzenesulfonyl chloride according to the procedure of Example 243 as a yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.51 (t, J=6.03 Hz, 4H), 3.52 (t, J=6.03Hz, 4H), 4.06 (s, 3H), 6.77-6.82 (m, 2H), 6.89-7.00 (m, 2H), 7.59 (dd,J=2.55 Hz, 8.79 Hz, 2H), 7.86 (d, J=2.49 Hz, 2H); HRMS found forC₁₈H₁₉BrN₂O₄S: 438.0215.

EXAMPLE 251{(4-Butyl-benzenesulfonyl)-[4-(4-oxo-piperidin-1-yl)-phenyl]-amino}-aceticacid ethyl ester

[0609] A solution of 0.12 g of4-butyl-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (whichwas obtained in Example 247), 0.038 mL of ethyl bromoacetate and 0.047 gof potassium carbonate in 10 mL acetonitrile was refluxed overnight. Thesolvent was removed in vacuo and the residue was purified by flashchromatography (8:1 Hexanes:EtOAc—1:1 Hexanes:EtOAc) to give 0.107 g ofthe title compound as a yellow gum; ¹H NMR (300 MHz, CDCl₃) δ0.93 (t,J=7.26 Hz, 3H), 1.19-1.26 (m, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H),2.52 (t, J=6.03 Hz, 4H), 2.67 (t, J-7.56 Hz, 2H), 3.60 (t, J=6.00 Hz,4H), 4.14 (q, J=7.14 Hz, 2H), 4.35 (s, 2H), 6.80-6.85 (m, 2H), 7.06-7.12(m, 2H), 7.24 (m, 2H), 7.59 (d, J=8.28 Hz, 2H); MS (ES) m/z: 473.0(MH⁺); HRMS found for C₂₅H₃₂N₂O₅S: 472.2028.

EXAMPLE 252{(3,4-Dimethoxy-benzenesulfonyl)-[4-(4-oxo-piperidin-1-yl)-phenyl]-amino}-aceticacid ethyl ester

[0610] The title compound was prepared from3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 242) according to the procedure ofExample 251 as a yellow gum; ¹H NMR (300 MHz, CDCl₃) δ1.26 (t, J=7.59Hz, 3H), 2.53 (t, J=6.09 Hz, 4H), 3.59 (t, J=6.00 Hz, 4H), 3.83 (s, 3H),3.94 (s, 3H), 4.11-4.19 (m, 2H), 4.36 (s, 1H), 6.80-6.91 (m, 2H),7.09-7.14 (m, 2H), 7.17 (d, J=2.16 Hz, 1H), 7.33 (d, J=2.16 Hz, 1H),7.36 (d, J=2.07 Hz, 1H); MS (ES) m/z: 477.0 (MH⁺); HRMS found forC₂₃H₂₈N₂O₇S: 477.1687.

EXAMPLE 253{(Butane-1sulfonyl)-[4-(4-oxo-piperidin-1-yl)-phenyl]-amino}-acetic acidbenzyl ester

[0611] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) and benzyl-2-bromoacetate according to the procedure of Example 251as an orange oil; ¹H NMR (300 MHz, CDCl₃) δ0.91 (t, J=7.29 Hz, 3H),1.34-1.47 (m, 2H), 1.75-1.86 (m, 2H), 2.55 (t, J=6.09 Hz, 4H), 3.17-3.23(m, 2H), 3.62 (t, J=6.00 Hz, 4H), 4.45 (s, 2H), 5.18 (s, 2H), 6.87-6.92(m, 2H), 7.30-7.40 (m, 7H); MS (ES) m/z: 459.0 (MH⁺); HRMS found forC₂₄H₃₀N₂O₅S: 459.1944.

EXAMPLE 254{(3,4-Dimethoxy-benzenesulfonyl)-[4-(4-oxo-piperidin-1-yl)-phenyl]-amino}-aceticacid benzyl ester

[0612] The title compound was prepared from3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 242) and benzyl-2-bromacetate accordingto the procedure of Example 251 as an orange gum; ¹H NMR (300 MHz,CDCl₃) δ2.53 (t, J=6.06 Hz, 4H), 3.59 (t, J=6.00 Hz, 4H), 3.79 (s, 3H),3.93 (s, 3H), 4.50 (s, 2H), 5.13 (s, 2H), 6.78-6.87 (m, 2H), 7.07-7.10(m, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.27- 7.37 (m, 7H); MS (ES) m/z: 539.0(MH⁺); HRMS found for C₂₈H₃₀N₂O₇S(MH⁺): 539.1842.

EXAMPLE 255N-{4-[4-(2-Hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-phenyl}-4-methoxy-benzenesulfonamide

[0613] A mixture of4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (whichwas obtained in Example 218) (0.16 g, 0.44 mmol) and2-amino-1-phenylethanol (0.18 g, 1.3 mmol) in 75 mL of methanol washydrogenated in the presence of 100 mg of 10% Pd/C under H₂ (5˜20 psi)for overnight. The catalyst was then removed by filtering through ashort pad of silica gel. The filtrate was concentrated and purified bysilica gel chromatography using 5-10% MeOH/CH₂Cl₂ as eluent to give 0.13g (61%) of the title compound as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.78-1.92 (m, 2 H), 2.50-2.80 (m, 5 H),3.60-3.70 (m, 2 H), 3.79 (s, 3 H), 4.56-4.60 (m, 1 H), 5.26 (brs, 1 H),6.76 (d, J=9.0 Hz, 2 H), 6.86 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2H), 7.20-7.25 (m, 1 H), 7.25-7.36 (m, 4 H), 7.58 (d, J=9.0 Hz, 2 H); MS(ES) m/z: 482.4 (MH⁺); HRMS Calcd. for C₂₆H₃₁N₃O₄S(M⁺): 481.2035. Found:481.2028.

EXAMPLE 256N-(4-{4-[2-Hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-4-methoxy-benzenesulfonamide

[0614] The title compound was prepared from4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (whichwas obtained in Example 218) and DL-norphenylephrine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.25-1.60 (m, 2 H), 2.00-2.15 (m, 2 H), 2.50-3.10 (m, 5 H), 3.60-3.70(m, 2 H), 3.79 (s, 3 H), 4.80-4.90 (m, 1 H), 6.05 (brs, 1 H), 6.70-6.80(m, 1 H), 6.80-6.85 (m, 4 H), 6.90 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0Hz, 2 H), 7.16 (t, J=7.7 Hz, 1 H), 7.60 (d, J=9.0 Hz, 2 H), 9.45 (s, 1H), 9.70 (s, 1 H); MS (ES) m/z: 498.5 (MH⁺); HRMS Calcd. forC₂₆H₃₁N₃O₅S(M⁺): 497.1984. Found: 497.1961.

EXAMPLE 257N-[4-(4-{4-[2-Hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-phenylsulfamoyl)-phenyl]-acetamide

[0615] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and DL-norphenylephrine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.35-1.50 (m, 2 H), 1.80-2.00 (m, 2 H), 2.06 (s, 3 H), 2.50-2.90 (m, 5H), 3.45-3.60 (m, 2 H), 4.55-4.65 (m, 1 H), 5.55 (brs, 1 H), 6.60-6.70(m, 1 H), 6.70-6.85 (m, 4 H), 6.86 (d, J=9.3 Hz, 2 H), 7.11 (t, J=7.8Hz, 1 H), 7.58 (d, J=8.7 Hz, 2 H), 7.68 (d, J=8.7 Hz, 2 H), 9.35 (s, 1H), 10.33 (s, 1 H); MS (ES) m/z: 525.4 (MH⁺); HRMS Calcd. forC₂₇H₃₃N₄O₅S (MH⁺): 525.2172. Found: 525.2177.

EXAMPLE 258N-(4-{4-[4-((2R)-2-Hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-phenylsulfamoyl}-phenyl)-acetamide

[0616] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and(1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained inExample 1) according to the procedure of Example 255 as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ1.55-1.75 (m, 2 H), 2.06 (s, 3 H), 2.00-2.15(m, 2 H), 2.50-3.20 (m, 5 H), 3.55-3.70 (m, 2 H), 4.90-5.00 (m, 1 H),6.00-6.20 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.89 (d, J=9.0 Hz, 2 H),7.25-7.52 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H),10.41 (s, 1 H); MS (ES) m/z: 509.2 (MH⁺); HRMS Calcd. for C₂₇H₃₃N₄O₄S(MH⁺): 509.2223. Found: 509.2194.

EXAMPLE 259N-(4-{[4-(4-{[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-1-piperidinyl)-anilino]sulfonyl}phenyl)acetamide

[0617] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and DL-octopamine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.55-1.75 (m, 2 H), 2.00-2.15 (m, 2 H), 2.06 (s, 3 H), 2.50-3.20 (m, 5H), 3.60-3.70 (m, 2 H), 4.80-4.90 (m, 1 H), 6.00 (brs, 1 H), 6.76 (d,J=9.7 Hz, 2 H), 6.80 (d, J=9.7 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.19(d, J=8.7 Hz, 2 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=8.7 Hz, 2 H),9.47 (s, 1 H), 10.43 (s, 1 H); MS (ES) m/z: 525.3 (MH⁺); HRMS Calcd. forC₂₇H₃₃N₄O₅S (MH⁺): 525.2172. Found: 525.2178.

EXAMPLE 260N-[4-(4-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide

[0618] A mixture of4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (whichwas obtained in Example 218) (0.288 g, 0.8 mmol) and(1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which wasobtained in Example 1) (0.832 g, 4.0 mmol) was dissolved in 50 mL ofmethanol and the pH was adjusted to 5 with triethylamine. After stirredat room temperature for one day acetic acid (1 mL) and NaCNBH₃ (50 mg,0.8 mmol) were then added. The reaction was stirred for another day, thesolvent was removed, and the residue was purified by thin layerchromatography (10% methanol/CH₂Cl₂) to give the title compound as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.60 (m, 2 H), 1.95-2.10(m, 2 H), 2.50-3.10 (m, 5 H), 3.50-3.70 (m, 2 H), 3.79 (s, 3 H),4.80-4.90 (m, 1 H), 6.79 (d, J=9.0 Hz, 2) 6.89 (d, J=9.0 Hz, 2 H), 7.05(d, J=9.0 Hz, 2 H), 7.30-7.50 (m, 4 H), 7.60 (d, J=9.0 Hz, 2 H), 9.60(brs, 1 H); MS (ES) m/z: 516.2 (MH⁺); HRMS Calcd. for C₂₆H₃₁ClN₃O₄S(MH⁺); 516.1724. Found: 516.1713.

EXAMPLE 261N-[4-(4-{[(2R)-2-Hydroxy-2-phenylethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide

[0619] The title compound was prepared from4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (whichwas obtained in Example 218) and(1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which wasobtained in Example 1) according to the procedure of Example 255 as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.55-1.75 (m, 2 H), 2.05-2.15(m, 2 H), 2.50-3.10 (m, 5 H), 3.50-3.70 (m, 2 H), 3.79 (s, 3 H),4.90-5.05 (m, 1 H), 6.10-6.20 (m, 1 H), 6.79 (d, J=9.0 Hz, 2 H), 6.89(d, J=9.0 Hz, 2 H), 7.05 (d, J=11.8 Hz, 2 H), 7.25-7.50 (m, 5 H), 7.60(d, J=11.8 Hz, 2 H), 9.70 (brs, 1 H); MS (ES) m/z: 482.2 (MH⁺); HRMSCalcd. for C₂₆H₃₂N₃O₄S (MH⁺): 482.2114. Found: 482.2120.

EXAMPLE 262N-(4-{[4-(4-{[2-Hydroxy-3-(4-methoxyphenoxy)propyl]amino}-1-pieridinyl)anilino]-sulfonyl}phenyl)acetamide

[0620] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and1-amino-3-(4-methoxy-phenoxy)-propan-2-ol according to the procedure ofExample 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.55-1.75 (m, 2H), 1.95-2.15 (m, 2 H), 2.06 (s, 3 H), 2.50-3.20 (m, 5 H), 3.85-3.95 (m,2 H), 4.10-4.20 (m, 1 H), 5.70 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H),6.80-6.95 (m, 6 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H),10.38 (s, 1 H); MS (ES) m/z: 569.6 (MH⁺); HRMS Calcd. for C₂₉H₃₇N₄O₆S(MH⁺): 569.2434. Found: 569.2418.

EXAMPLE 263N-(4-{[4-(4-{[(2R)-2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide

[0621] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and L-norepinephrine according to theprocedure of Example 255 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.50-1.72 (m, 2 H), 1.95-2.10 (m, 2 H), 2.06 (s, 3 H), 2.50-3.20 (m, 5H), 3.55-3.70 (m, 2 H), 4.05-4.20 (brs, 1), 4.60-4.75 (m, 1 H),5.75-5.90 (brs, 1 H), 6.60-6.90 (m, 7 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70(d, J =9.0 Hz, 2 H), 8.93 (brs, 1 H), 10.42 (s, 1 H); MS (ES) m/z: 541.6(MH⁺); HRMS Calcd. for C₂₇H₃₃N₄O₆S (MH⁺): 541.2121. Found: 541.2133.

EXAMPLE 264N-(4-{[2-(4-{[2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]-sulfonyl}phenyl)acetamide

[0622] The title compound was prepared fromN-{4-[2-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 222) and DL-norphenylephrine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.70-1.90 (m, 2 H), 1.90-2.10 (m, 2 H), 2.06 (s, 3 H), 2.50-3.20 (m, 7H), 4.75-4.95 (m, 1 H), 6.10 (brs, 1 H), 6.50-7.40 (m, 8 H), 7.65-7.80(m, 4 H), 9.48 (s, 1 H), 10.42 (s, 1 H); MS (ES) m/z: 525.6 (MH⁺); HRMSCalcd. for C₂₇H₃₃N₄O₅S (MH⁺): 525.2172. Found: 525.2164.

EXAMPLE 265N-(4-{[2-(4-{[(2R)-2-(3,4-Dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)-anilino]sulfonyl}phenyl)acetamide

[0623] The title compound was prepared fromN-}(4-[2-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide(which was obtained in Example 222) and L-norepinephrine according tothe procedure of Example 255 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.30-1.52 (m, 2 H), 1.70-1.90 (m, 2 H), 1.89 (s, 3 H), 2.50-3.50 (m, 7H), 4.40-4.55 (m, 1 H), 6.00 (brs, 1 H) 6.50-6.80 (m, 3 H), 6.95-7.15(m, 2 H), 7.25-7.40 (m, 2 H), 7.60-7.57 (m, 4 H), 10.30 (s, 1 H); MS(ES) m/z: 541.4 (MH⁺); HRMS Calcd. for C₂₇H₃₃N₄O₆S (MH⁺): 541.2121.Found: 541.2110.

EXAMPLE 266N-[4-(4-{[(2R)-2-(3,4-Dihydroxyphenyl)-2-hydroxyethylamino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide

[0624] The title compound was prepared from4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfomide (whichwas obtained in Example 218) and L-norepinephrine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.40-1.55 (m, 2 H), 1.90-2.05 (m, 2 H), 2.50-3.00 (m, 5 H), 3.50-3.75(m, 2 H), 3.79 (s, 3 H), 4.50-4.65 (m, 1 H), 6.60 (d, J=8.0 Hz, 1 H),6.68 (d, J=8.0 Hz, 1 H), 6.76-6.80 (m, 3 H), 6.88 (d, J=9.0 Hz, 2 H),7.04 (d, J=7.8 Hz, 2 H), 7.61 (d, J=7.8 Hz, 2 H), 8.85 (s, 1 H); MS (ES)m/z: 513.9 (MH⁺); HRMS Calcd. for C₂₆H₃₂N₃O₆S (MH⁺): 514.2011. Found:514.2000.

EXAMPLE 267N-(4-{[4-(4-{[2-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide

[0625] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216)and DL-normetanephrine according to theprocedure of Example 255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.40-1.60 (m, 2 H), 1.90-2.06 (m, 2 H), 2.06 (s, 3 H), 2.50-3.50 (m, 5H), 3.55-3.65 (m, 2 H), 3.77 (s, 3 H), 4.70-4.80 (m, 1 H), 5.70-5.85(brs, 1 H), 6.70-6.90 (m, 7 H), 7.59 (d, J=8.7 Hz, 2 H), 7.69 (d, J=8.7Hz, 2 H), 8.95 (brs, 1 H), 10.37 (s, 1 H); MS (ES) m/z: 555.2 (MH⁺);HRMS Calcd. for C₂₈H₃₅N₄O₆S (MH⁺): 555.2277. Found: 555.2265.

EXAMPLE 268N-(4-{[4-(4-{[2-(2,4-Dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)-anilino]sulfonyl}phenyl)acetamide

[0626] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and2-amino-1-(2,4-dihydroxy-phenyl)-ethanol according to the procedure ofExample 255 as a pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.55-1.75 (m, 2 H), 1.95-2.15 (m, 2 H), 2.08 (s, 3 H), 2.50-3.20 (m, 5H), 3.60-3.70 (m, 2 H), 5.04-5.10 (m, 1 H), 6.65-6.75 (m, 1 H), 6.24(dd, J=8.1, 2.1 Hz, 1 H), 6.32 (d, J=2.1 Hz, 1 H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2 H), 7.12 (d, J=8.1 Hz, 1 H), 7.59 (d, J=9.0 Hz,2H), 7.70 (d, J=9.0 Hz, 2 H), 9.26 (s, 1 H), 9.71 (brs, 1 H), 10.44 (s,1 H); MS (ES) m/z: 541.4 (MH⁺); HRMS Calcd. for C₂₇H₃₃N₄O₆S (MH⁺):541.2121. Found: 541.2084.

EXAMPLE 269N-(4-{[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide

[0627] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and(2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained inExample 5) according to the procedure of Example 255 as a grey solid; ¹HNMR (300 MHz, DMSO-d₆) δ1.40-1.65 (m, 2 H), 1.95-2.15 (m, 2 H), 2.06 (s,3 H), 2.50-3.20 (m, 5 H), 3.55-3.70 (m, 2 H), 3.80-3.90 (m, 1 H),4.05-4.20 (m, 1 H), 5.70 (brs, 1 H), 6.67 (d, J=9.0 Hz, 2 H), 6.76 (d,J=9.0 Hz, 2 H), 6.78 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.58(d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2H), 8.97 (s, 1 H), 10.37 (s, 1H); MS (ES) m/z: 555.1 (MH⁺); HRMS Calcd. for C₂₈H₃₅N₄O₆S (MH⁺):555.2277. Found: 555.2267.

EXAMPLE 270N-{4-[(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide

[0628] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) andN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Example 7) according to the procedure of Example255 as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.35-1.60 (m, 2 H),1.90-2.10 (m, 2 H), 2.06 (s, 3 H), 2.50-3.00 (m, 5 H), 3.16 (s, 3 H),3.55-3.70 (m, 2 H), 4.65-4.80 (m, 1 H), 6.00 (brs, 1 H), 6.70-7.25 (m, 7H), 7.58 (d, J=9.0 Hz, 2 H), 7.68 (d, J=9.0 Hz, 2 H), 10.39 (s, 1 H); MS(ES) m/z: 618.1 (MH⁺); HRMS Calcd. for C₂₈H₃₆N₅O₇S₂ (MH⁺): 618.2056.Found: 618.2036.

EXAMPLE 2714-{[(Hexylamino)carbonyl]amino}-N-[4-(4-{[2-hydroxy-2-(6-methyl-3-pyridinyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide

[0629] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benezenesulfonamide(which was obtained in Example 225) and2-amino-1-(6-methyl-pyridin-3-yl)ethanol according to the procedure ofExample 255 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=6.8Hz, 3 H), 1.20-3.30 (m, 19 H), 2.45 (s, 3 H), 3.50-3.75 (m, 2 H),4.70-4.80 (m, 1 H), 6.41 (t, J=5.5 Hz, 1 H), 6.78 (d, J=9.1 Hz, 2 H),6.87 (d, J=9.1 Hz, 2 H), 7.21(d, J=8.0 Hz, 1 H), 7.46(d, J=9.2 Hz, 2 H),7.48(d, J=9.2 Hz, 2 H), 7.64(dd, J=8.0, 2.0 Hz, 1 H), 8.43(d, J=2.0 Hz,1 H), 9.00 (s, 1 H), 9.50 (brs, 1 H), 11.10 (s, 1 H); MS (ES) m/z: 609.3(MH⁺); HRMS Calcd. for C₃₂H₄₅N₆O₄S (MH⁺): 609.3223. Found: 609.3235.

EXAMPLE 272N-(4-{[4-(4-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]-sulfonyl}phenyl)acetamidesulfonylphenyl)acetamide

[0630] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Example 3) according to the procedure of Example255 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.65 (m, 2 H),1.95-2.10 (m, 2 H), 2.06 (s, 3 H), 2.50-3.20 (m, 5 H), 3.55-3.75 (m, 2H), 3.96 (d, J=5.2 Hz, 2 H), 4.15-4.25 (m, 1 H), 5.70(brs, 1 H), 6.80(d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 6.90-7.00 (m, 3 H),7.25-7.35 (m, 2 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H),9.70 (s, 1 H), 10.37 (s, 1 H), MS (ES) m/z: 539.1 (MH⁺); HRMS Calcd. forC₂₈H₃₅N₄O₅S (MH⁺): 539.2328. Found: 539.2357.

EXAMPLE 2735-[2-({1-[4-({[4-(Acetylamino)phenyl]sulfonyl}amino)phenyl]-4-piperidinyl}amino)-1-hydroxyethyl]-1H-indole-7-carboxamide

[0631] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl{-acetamide (whichwas obtained in Example 216) and5-(2-amino-1-hydroxy-ethyl)-1H-indole-7-carboxamide according to theprocedure of Example 255 as a pale grey solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.60-1.80 (m, 2 H), 2.00-2.15 (m, 2 H), 2.06 (s, 3 H), 2.50-2.70 (m, 2H), 3.10-3.20 (m, 3 H), 3.60-3.75 (m, 2 H), 4.95-5.05 (m, 1 H), 6.13(brs, 1 H), 6.49 (t, J=2.7 Hz, 1 H), 6.81 (d, J=9.0 Hz, 2 H), 6.88 (d,J=9.0 Hz, 2 H), 7.35 (t, J=2.7 Hz, 1 H), 7.42 (brs, 1 H), 7.59 (d, J=9.0Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 7.77 (s, 1 H), 8.11 (s, 1 H), 9.72(s, 1 H), 10.40 (s, 1 H); MS (ES) m/z: 591.1 (MH⁺); HRMS Calcd. forC₃₀H₃₅N₆O₅S (MH⁺): 591.2390. Found: 591.2392.

EXAMPLE 274N-[4-({4-([4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide

[0632] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 255 as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.60-1.80 (m, 2 H), 2.00-2.15(m, 2 H), 2.06 (s, 3 H), 2.50-2.70 (m, 2 H), 2.90-3.20 (m, 3 H),3.60-3.75 (m, 2 H), 4.15-4.25 (m, 1 H), 5.70 (brs, 1 H), 6.61 (t, J=8.7Hz, 1 H), 6.80-6.92 (m, 5 H), 7.60 (d, J=9.0 Hz, 2 H), 7.70 (d, J=9.0Hz, 2 H), 9.72 (brs, 1 H), 10.42 (s, 1 H), 10.65 (s, 1 H), 10.80 (s, 1);MS (ES) m/z: 595.2 (MH⁺); HRMS Calcd. for C₂₉H₃₅N₆O₆S (MH⁺): 595.2339.Found: 595.2332.

EXAMPLE 2754-{[(Hexylamino)carbonyl]amino}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0633] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 225) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 255 as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=6.8 Hz, 3 H),1.20-1.60 (m, 10 H), 1.90-2.05 (m, 2 H), 2.50-3.50 (m, 9 H), 3.50-3.65(m, 1 H), 3.95-4.05 (m, 2 H), 6.43 (t, J=5.6 Hz, 1 H), 6.58 (d, J=7.8Hz, 1 H), 6.61 (d, J=8.2 Hz, 1 H), 6.70-6.89 (m, 5 H), 7.46(d, J=9.0 Hz,2 H), 7.51(d, J=9.0 Hz, 2 H), 9.06 (s, 1 H), 9.60 (brs, 1 H), 10.60 (s,1 H), 10.75 (s, 1 H); MS (ES) m/z: 680.3 (MH⁺); HRMS Calcd. forC₃₄H₄₆N₇O₆S (MH⁺): 680.3230. Found: 680.3221.

EXAMPLE 2764-{[(Hexylamino)carbonyl]amino}-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide

[0634] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 225) andN-[2-benzyloxy-5-(2-amino-(1R)-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Example 8) according to the procedure of Example255 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=6.9 Hz, 3 H),1.20-1.80 (m, 10 H), 1.95-2.15 (m, 2 H), 2.50-3.30 (m, 7 H), 2.97 (s, 3H), 3.55-3.70 (m, 2 H), 4.70-4.85 (m, 1 H), 5.90-6.10 (m, 1 H), 6.48 (t,J=5.6 Hz, 1 H), 6.83 (d, J=9.2 Hz, 2 H), 6.90 (d, J=9.2 Hz, 2 H), 6.91(d, J=8.4 Hz, 1 H), 7.07(dd, J=8.4, 2.0 Hz, 1 H), 7.24 (d, J=2.0 Hz, 1H), 7.46(d, J=9.2 Hz, 2 H), 7.51 (d, J=9.2 Hz, 1 H), 8.50-8.90 (brs, 1H), 9.39 (s, 1 H), 9.61 (s, 1 H); MS (ES) m/z: 703.4 (MH⁺); HRMS Calcd.for C₃₃H₄₇N₆O₇S₂(MH⁺): 703.2948. Found: 703.2946.

EXAMPLE 2774-[4-(3-Cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-{4-[4-({(2S)-2-hydroxy-3-[2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0635] The title compound was prepared from4-[4-(3-cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 226) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat No. 5,786,356/1998) according to the procedure of Example 255 as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.90-4.00 (m, 29 H), 5.10-5.30(m, 1 H), 6.58 (d, J=7.9 Hz, 1 H), 6.61 (d, J=7.9 Hz, 1 H), 6.81 (d,J=8.9 Hz, 2 H), 6.89(d, J=8.9 Hz, 2 H), 6.90 (dd, J=7.9, 7.9 Hz, 1 H),7.86 (d, J=8.5 Hz, 2 H), 8.07 (d, J=8.5 Hz, 2 H), 10.70 (s, 1 H), 10.80(s, 1 H); MS (ES) m/z: 732.3 (MH⁺); HRMS Calcd. for C₃₆H₄₆N₉O₆S (MH⁺):732.3292. Found: 732.3294.

EXAMPLE 278N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamide

[0636] 5-Pyridin-2-yl-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example227) (0.21 g, 0.5 mmol) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) (0.11 g, 0.5 mmol) were mixed indimethylformamide (10 mL) and then treated with sodiumtriacetoxyborohydride, (0.16 g, 0.75 mmol) and acetic acid (0.045 g,0.75 mmol). After stirring at room temperature under a nitrogenatmosphere for one day the mixture was quenched with 1N NaOH and thenpoured into a saturated aqueous NaHCO_(3.) The precipitate which formedwas collected and purified by preparative thin layer chromatography (16%MeOH/CH₂CH₂) to give the titled compound as a pale yellowish solid; ¹HNMR (300 MHz, DMSO-d₆) δ1.25-1.40 (m, 2 H), 1.80-1.90 (m, 2 H),2.50-2.90 (m, 5 H), 3.53 (brd, J=9.0 Hz, 2 H), 3.85-4.00 (m, 2 H),4.00-4.10 (m, 1 H), 4.91 (brs, 1 H), 6.56 (d, J=5.7 Hz, 1 H), 6.61 (d,J=5.7 Hz, 1 H), 6.80-6.90 (m, 3 H), 6.96 (d, J=6.6 Hz, 2 H), 7.36 (dd,J=3.3, 1.2 Hz, 1 H), 7.41 (d, J=3.0 Hz, 1 H), 7.75 (d, J=3.0 Hz, 1 H),7.88 (dd, J=6.0, 1.2 Hz, 1 H), 7.98 (d, J=6.0 Hz, 1 H), 8.54(d, J=3.3Hz, 1 H), 10.60 (s, 1 H), 10.70 (s, 1 H); MS (ES) m/z: 621.0 (MH⁺); HRMSCalcd. for C₃₀H₃₃N₆O₅S₂ (MH⁺): 621.1954. Found: 621.1952.

EXAMPLE 279N-[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0637] The title compound was prepared according to the procedure ofExample 278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.25(m, 2H), 1.75 (m, 2H), 2.27 (m, 2H), 2.52-2.61 (m, 2H), 2.65 (m, 1H),2.73 (m, 1H), 3.15-3.17 (m, 2H), 3.54-3.58 (m, 2H), 3.72 (s, 3H), 3.78(s, 3H), 3.81-3.83 (m, 1 H) 3.86-3.89 (m, 2H), 6.54-6.69 (m, 1H),6.72-6.81 (m, 6H), 6.89 (d, 1H, J=9.0 Hz), 7.03 (d, 2H, J=8.52 Hz), 7.16(d, 1H, J=2.07 Hz), 7.20-7.24 (dd, 1H, J=2.04 Hz, 8.37 Hz), 8.92 (s,1H), 9.61 (brs, 1H); MS (ES) m/z: 558.0 (MH⁺); HRMS found forC₃₄H₃₈N₄O₆S: 558.2271.

EXAMPLE 280N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-dimethoxybenzenesulfonamide

[0638] The title compound was prepared according to the procedure ofExample 278 as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.59 (m,2H), 1.95-2.05 (m, 2H), 2.54-2.62 (m, 2H), 2.72 (m, 2H), 2.94 (s, 3H),3.00-3.04 (m, 2H), 3.56 (brd, 2H, J=12.00 Hz), 3.72 (s, 3H), 3.78 (s,3H), 4.10 (brs, 1H), 4.70 (brd, 1H, J=7.8 Hz), 5.95 (brs, 1H), 6.81 (d,1H, J=9.09 Hz), 6.86-6.92 (m, 2H), 7.01-7.04 (m, 2H), 7.17-7.24 (m, 5H),8.45 (brs, 1H), 9.16 (s, 1H); MS (ES) m/z: 621.0 (MH⁺); HRMS found forC₂₈H₃₆N₄O₈S₂: 621.2079.

EXAMPLE 2814-Butoxy-N-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-benzenesulfonamide

[0639] The title compound was prepared according to the procedure ofExample 278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.915 (t,J=7.32 Hz, 3H), 1.07-1.14 (m, 2H), 1.34-1.47 (m, 2H), 1.63-1.73 (m, 2H),1.91 (m, 3H), 2.27 (m, 2H), 2.55-2.63 (m, 2H), 2.73 (m, 2H), 2.8 (m,2H), 2.93 (s, 3H), 3.16 (m, 2H), 3.53-3.58 (m, 2H), 3.99 (t, J=6.39 Hz,2H), 4.58 (brs, 1H), 6.78 (d, J=9.09 Hz, 2H), 6.83-6.89 (m, 3H),7.00-7.05 (m, 3H), 7.20 (s, 2H), 7.57 (d, J=8.82 Hz, 2H), 9.64 (brs,1H); MS (ES) m/z: 633.1 (MH⁺); HRMS found for C₃₀H₄₀N₄O₇S₂: 633.2401.

EXAMPLE 282N-(4-{[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)-anilino]sulfonyl}phenyl)acetamide

[0640] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine (Berridge et al.,Int. J. Radial. Appl. Instrum., 1992, 563) according to the procedure ofExample 255 as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.55-1.75(m, 2 H), 2.00-2.15 (m, 2 H), 2.06 (s, 3 H), 2.50-2.70 (m, 2 H),3.00-3.50 (m, 3 H), 3.60-3.70 (m, 2 H), 4.10-4.25 (m, 2 H), 4.35-4.50(m, 1 H), 5.97 (brs, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 6.80 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.0Hz, 2 H), 7.10-7.50 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H),7.69 (d, J=8.7 Hz, 2 H), 8.22 (d, J=7.8 Hz, 1 H), 9.71 (s, 1 H), 10.40(s, 1 H), 11.32 (s, 1 H); MS (ES) m/z: 627.9 (MH⁺); HRMS Calcd. forC₃₄H₃₈N₅O₅S (MH⁺): 628.2594. Found: 628.2593.

EXAMPLE 2835-Chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3-methyl-1-benzothiophene-2-sulfonamide

[0641] The title compound was prepared according to the procedure ofExample 278 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.33-1.36 (m,2H), 1.79-1.91 (m, 2H), 2.21-2.27 (m, 2H), 2.40 (s, 3H), 2.58-2.66 (m,2H), 2.73 (m, 2H), 2.84-2.88 (m, 2H), 3.46-3.56 (m, 2H), 3.92-4.03 (m,2H), 5.03 (brs, 1H), 6.55-6.63 (m, 2H), 6.81 (t, J=9.3 Hz, 3H),6.86-7.00 (m, 2H), 7.55 (dd, J=1.8 Hz, 8.7 Hz, 1H), 7.98 (d, J=1.8 Hz,1H), 8.04 (d, J=8.7 Hz, 1H), 10.54 (s, 1H), 10.7 (s, 1 H); MS (ES) m/z:642.0 (MH⁺); HRMS found for C₃₀H₃₂ClN₅O₅S₂: 642.1598.

EXAMPLE 2844-Cyano-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0642] The title compound was prepared according to the procedure ofExample 278 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.27-1.37 (m,2H), 1.85-1.90 (m, 2H), 2.56-2.75 (m, 2H), 2.79-2.80 (m, 2H), 2.82-2.84(m, 2H), 3.50-3.51 (m, 2H), 3.87-3.96 (m, 2H), 3.99-4.03 (m, 2H), 4.90(brs, 1H), 6.56-6.63 (m, 2H), 6.67-6.87 (m, 5H), 7.81 (d, 2H), 8.02 (d,2H), 10.58 (s, 1H), 10.92 (brs, 1H); MS (ES) m/z: 563.0 (MH⁺); HRMSfound for C₃₀H₃₂N₅O₅S₂ : 563.2090.

EXAMPLE 2854-Cyano-N-[(4-cyanophenyl)sulfonyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0643] The title compound was prepared according to the procedure ofExample 278 as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.23-1.34(m, 2H), 1.90 (m, 2H), 2.26-2.28 (m, 2H), 2.63-2.75 (m, 2H), 2.79-2.87(m, 2H), 3.72-3.76 (m, 2H), 3.89-3.97 (m, 2H), 4.01-4.05 (m, 2H), 4.92(brs, 1H), 6.57 (d, J=7.59 Hz, 1H), 6.62 (d, J=8.19 Hz, 1H), 6.79-6.84(m, 4H), 6.87-6.92 (m, 4H), 7.99 (d, 2H), 8.21 (d, 2H), 10.55 (s, 1H),10.7 (brs, 1H); MS (ES) m/z: 728.0 (MH⁺); HRMS found for C₃₀H₃₂N₅O₅S₂:728.1970.

EXAMPLE 2863-Bromo-5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide

[0644] The title compound was prepared according to the procedure ofExample 278 as an orange-yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ1.35-1.44 (m, 2H), 1.84-2.05 (m, 2H), 2.60-2.67 (m, 2H), 2.72-2.77 (m,2H), 2.92-2.96 (m, 2H), 3.15-3.17 (m, 2H), 3.55-3.59 (m, 2H), 3.95-4.02(m, 2H), 5.12 (brs, 1H), 6.56-6.64 (m, 1H), 6.82 (m, 1H), 6.88 (s, 2H),6.92 (d, J=8.97 Hz, 4H), 7.38 (s, 1H), 10.6 (s, 1H), 10.7 (s, 1H); MS(ES) m/z: 657.8 (MH⁺); HRMS found for C₂₅H₂₇BrClN₅O₅S₂ : 656.0444.

EXAMPLE 287N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-5-(3-isoxazolyl)-2-thiophenesulfonamide

[0645] The title compound was prepared according to the procedure ofExample 278 as a red-brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.36-1.40(m, 2H), 1.90 (m, 2H), 2.27 (m, 1H), 2.61-2.69 (m, 2H), 2.72-2.76 (m,2H), 2.87-2.91 (m, 2H), 3.55-3.60 (m, 2H), 3.93-4.02 (m, 2H), 5.07 (brs,1H), 6.59 (q, 2H), 6.81-6.89 (m, 4H), 6.94 (d, J=9.03 Hz, 2H), 7.06 (d,J=1.92 Hz, 1H), 7.47 (d, J=4.02 Hz, 1H), 7.66 (d, J=3.93 Hz, 1H), 8.71(d, J=1.98 Hz, 1H), 10.55 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 611.0(MH⁺).

EXAMPLE 2884-[4-(3-Cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-N-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethaylamino]-piperidin-1-yl}-phenyl)-benzenesulfonamide

[0646] The title compound was prepared from4-[4-(cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazo-1-yl]-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 226) andN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Example 7) according to the procedure of Example255 as a grey solid; MS (ES) m/z: 754.9 (MH⁺); HRMS Calcd. forC₃₅H₄₇N₈O₇S₂(MH⁺): 755.3009. Found: 755.2997.

EXAMPLE 2894-Butoxy-N-(4-{4-[3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamino]-piperidin-1-yl}-phenyl)-benzenesulfonamide

[0647] The title compound was prepared according to the procedure ofExample 278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.91 (t,J=7.32 Hz, 3H), 1.34-1.46 (m, 2H), 1.62-1.72 (m, 2H), 1.90 (m, 2H),2.57-2.65, (m, 2H), 2.83-2.85 (m, 2H), 2.96-2.99 (m, 2H), 3.17 (d,J=5.13 Hz, 2H), 3.49-3.54 (m, 2H), 3.99 (t, J=6.45 Hz, 2H), 4.11-4.16(m, 2H), 5.25 (brs, 1H), 5.76 (s, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.76 (d,J=9.3 Hz, 2H), 6.87 (d, J=9.0 Hz, 2H), 7.00-7.15 (m, 4H), 7.25-7.36 (m,2H), 7.44 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 8.20 (d, J=7.8 Hz,1H), 9.63 (brs, 1H), 11.25 (s, 1H); MS (ES) m/z: 643.2 (MH⁺); HRMS foundfor C₃₆H₄₂N₄O₅S: 643.2961.

EXAMPLE 290N-[4-(4-{4-[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxy-propylamino]-piperidin-1-yl}-phenyl)-4-(3-hexyl-ureido)-benzenesulfonamide

[0648] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzensulfonamide(which was obtained in Example 225) and(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine (Berridge et al.,Int. J. Radial. Appl. Instrum., 1992, 563) according to the procedure ofExample 255 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t,J=6.8 Hz, 3 H), 1.20-1.45 (m, 8 H), 1.40-1.55 (m, 2 H), 1.90-2.05 (m, 2H), 2.50-2.75 (m, 2 H), 2.90-3.50 (m, 7 H), 3.60-3.70 (m, 2 H),4.10-4.35 (m, 3 H), 6.40 (t, J=5.6 Hz, 1 H), 6.68 (d, J=8.0 Hz, 1 H),6.78 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 1 H), 7.14 (t, J=7.2 Hz, 1 H), 7.21 (d, J=8.0 Hz,1 H), 7.33 (t, J=5.2 Hz, 1 H), 7.40-7.60 (m, 5 H), 8.21 (d, J=7.7 Hz, 1H), 9.01 (s, 1 H), 9.59 (brs, 1 H), 11.30 (s, 1 H); MS (ES) m/z: 713.1(MH⁺); HRMS Calcd. for C₃₉H₄₉N₆O₅S (MH⁺): 713.3485. Found: 713.3501.

EXAMPLE 291N-{4-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide

[0649] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide(which was obtained in Example 8) according to the procedure of Example255 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.70 (m, 2H), 1.90-2.10 (m, 2 H), 2.06 (s, 3 H), 2.50-2.65 (m, 2 H), 2.90-3.15 (m,3 H), 2.94 (s, 3 H), 3.55-3.70 (m, 2 H), 4.65-4.80 (m, 1 H), 6.79 (d,J=9.0 Hz, 2 H), 6.97 (d, J=9.0 Hz, 2 H), 7.00 (d, J=8.0 Hz, 1 H), 7.06(dd, J=8.0, 1.2 Hz, 1 H), 7.22 (d, J=1.2 Hz, 1 H), 7.40 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2 H), 10.42 (s, 1 H), 10.44 (s, 1 H); MS (ES)m/z: 618.0 (MH⁺); HRMS Calcd. for C₂₈H₃₆N₅O₇S₂ (MH⁺): 618.2056. Found:618.2056.

EXAMPLE 292N-[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0650] The title compound was prepared according to the procedure ofExample 278 as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.38 (m, 2H),1.90 (m, 2H), 2.59-2.65 (m, 2H), 2.84 (m, 2H), 2.97 (m, 2H), 3.50-3.54(m, 2H), 3.71 (s, 3H), 3.78 (s, 3H), 4.10-4.14 (m, 2H), 4.16-4.17 (m,2H), 5.2 (brs, 1H), 6.68 (d, J=6.0 Hz, 1H), 6.77 (d, J=6.9 Hz, 2H), 6.88(d, J=6.9 Hz, 2H), 7.01-7.07 (q, 2H), 7.10-7.17 (m, 2H), 7.21-7.23 (dd,J=1.8 Hz, 6.3 Hz, 1H), 7.26-7.35 (m, 2H), 7.44 (d, J=6.0 Hz, 1H), 8.20(d, J=5.7 Hz, 1H), 11.2 (s, 1H); MS (ES) m/z: 631.2 (MH⁺); HRMS foundfor C₃₄H₃₈N₄O₆S: 631.2596.

EXAMPLE 293N-[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide

[0651] The title compound was prepared from5-pyridin-2-yl-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide(which was obtained in Example227) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtainedin Example 5) according to the procedure of Example 278 as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.80-1.90 (m, 2H), 2.40-2.80 (m, 5 H), 3.50-3.60 (m, 2 H), 3.70-3.90 (m, 3 H), 4.99(brs, 1 H), 6.66 (d, J=8.0 Hz, 2 H), 6.75 (d, J=8.0 Hz, 2 H), 6.83 (d,J=9.0 Hz, 2 H), 6.96 (d, J=9.0 Hz, 1 H), 7.36 (dd, J=4.4, 1.7 Hz, 1 H),7.41 (d, J=4.0 Hz, 1 H), 7.76 (d, J=4.0 Hz, 1 H), 7.88 (dd, J=8.0, 1.7Hz, 1 H), 8.00(d, J=8.0 Hz, 1 H), 8.54 (d, J=4.4 Hz, 1 H), 8.89 (s, 1H); MS (ES) m/z: 580.9 (MH⁺); HRMS Calcd. for C₂₉H₃₃N₄O₅S₂ (MH⁺):581.1892. Found: 581.1910.

EXAMPLE 294N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-5-(2-pyridinyl)-2-thiophenesulfonamide

[0652] The title compound was prepared from5-pyridin-2-yl-thiophene-2-sulfonic acid[4-(4-hydroxy-ethyl)-4-oxo-piperidin-1-yl)-phenyl]-amide(which wasobtained in Example 227) andN-[5-(2-amino-1hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2H), 1.80-1.90 (m, 2 H), 2.45-2.75 (m, 5 H), 2.91 (s, 3 H), 3.40-3.60 (m,2 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 6.80 (d, J=8.3 Hz, 1 H), 6.82 (d,J,=8.0 Hz, 2 H), 6.95 (d, J=8.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H),7.17 (d, J=2.0 Hz, 1 H), 7.37 (dd, J=4.8, 1.7 Hz, 1 H), 7.40(d, J=3.9Hz, 1 H), 7.75 (d, J=3.9 Hz, 1 H), 7.88(dd, J=8.0, 1.7 Hz, 1 H), 7.98(d, J=8.0 Hz, 1 H), 8.54 (brd, J=4.8 Hz, 1 H); MS (ES) m/z: 644.1 (MH⁺);HRMS Calcd. for C₂₉H₃₄N₅O₆S₃ (MH⁺): 644.1671. Found: 644.1663.

EXAMPLE 295N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide

[0653] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) andN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Example 7) according to the procedure of Example255 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.83(t, J=7.2 Hz,3 H), 1.20-1.40 (m, 2 H), 1.50-1.70 (m, 4 H), 1.95-2.10 (m, 2 H),2.40-2.60 (m, 2 H), 2.94 (s, 3 H), 2.90-3.20 (m, 5 H), 3.62-3.75 (m, 2H), 4.70-4.80 (m, 1 H), 5.95 (brs, 1 H), 6.85-6.95 (m, 3 H), 7.00-7.10(m, 3 H), 7.24 (d, J=2.0 Hz, 1 H), 8.70 (brs, 1 H), 9.33 (brs, 1 H); MS(ES) m/z: 541.0 (MH⁺); HRMS Calcd. for C₂₄H₃₇N₄O₆S₂ (MH⁺): 541.2155.Found: 541.2161.

EXAMPLE 296N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide

[0654] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 255 as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.83(t, J=7.2 Hz, 3 H),1.20-1.70 (m, 6 H), 1.95-2.10 (m, 2 H), 2.67 (brt, J=11.7 Hz, 2 H),2.70-3.20 (m, 7 H), 3.62-3.75 (m, 2 H), 3.95-4.10 (m, 3 H), 6.59 (d,J=7.5 Hz, 1 H), 6.63 (d, J=8.0 Hz, 1 H), 6.80-7.00 (m, 3 H), 7.06 (d,J=9.0 Hz, 2 H), 9.32 (brs, 1 H), 10.61 (brs, 1 H), 10.73 (brs, 1 H); MS(ES) m/z: 518.1 (MH⁺); HRMS Calcd. for C₂₅H₃₆N₅O₅S (MH⁺): 518.2437.Found: 518.2452.

EXAMPLE 297N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-octanesulfonamide

[0655] The title compound was prepared from octane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example230) andN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Example 7) according to the procedure of Example255 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.84(t, J=7.0 Hz,3 H), 1.15-1.40 (m, 12 H) 1.50-1.70 (m, 2 H), 1.80-1.95 (m, 2 H),2.50-2.92 (m, 7 H), 3.50-3.65 (m, 2 H), 4.49 (dd, J=8.0, 4.1 Hz, 1 H),6.82 (d, J=8.3 Hz, 1 H), 6.88 (d, J=8.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0Hz, 1 H), 7.04 (d, J=8.0 Hz, 2 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z:597.1 (MH⁺); HRMS Calcd. for C₂₈H₄₅N₄O₆S₂ (MH⁺): 597.2781. Found:597.2776.

EXAMPLE 298N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-octanesulfonamide

[0656] The title compound was prepared from octane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example230) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 255 as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.85(t, J=7.0 Hz, 3 H),1.10-1.40 (m, 10 H), 1.50-1.70 (m, 4 H), 1.95-2.16 (m, 2 H), 2.67 (brt,J=11.1 Hz, 2 H), 2.93 (brt, J=7.9 Hz, 2 H), 2.95-3.20 (m, 3 H),3.62-3.75 (m, 2 H), 4.00-4.12 (m, 2 H), 4.12-4.30 (m, 1 H), 6.59 (d,J=7.8 Hz, 1 H), 6.63 (d, J=8.3 Hz, 1 H), 6.80-7.00 (m, 3 H), 7.07 (d,J=9.0 Hz, 2 H), 9.33 (brs, 1 H), 10.60 (brs, 1 H), 10.75 (brs, 1 H); MS(ES) m/z: 574.1 (MH⁺); HRMS Calcd. for C₂₉H₄₄N₅O₅S (MH⁺): 574.3063.Found: 574.3084.

EXAMPLE 299N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl-amino)-1-piperidinyl]phenyl}-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide

[0657] The title compound was prepared from5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example229) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 278 as ayellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.30-1.50 (m, 2 H),1.80-2.00 (m, 2 H), 2.50-3.00 (m, 5 H), 3.54 (brd, J=9.3 Hz, 2 H),3.90-4.10 (m, 3 H), 6.57 (d, J=6.0 Hz, 1 H); 6.62 (d, J=6.0 Hz, 1 H),6.62-6.90 (m, 5 H), 7.92 (d, J=2.0 Hz, 1 H), 8.39 (d, J=9.0 Hz, 1 H),8.48 (d, J=2.0 Hz, 1 H), 8.62 (dd, J=9.0, 2.0 Hz, 1 H), 9.23 (s, 1 H),10.56 (s, 1 H), 10.69 (s, 1 H); MS (ES) m/z: 752.9 (MH⁺); HRMS Calcd.for C₃₁H₃₂F₃N₆O₇S₃ (MH⁺): 753.1447. Found: 753.1468.

EXAMPLE 300N-[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide

[0658] The title compound was prepared from5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example229) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtainedin Example 5) according to the procedure of Example 278 as a grey solid;¹H NMR (300 MHz, DMSO-d₆) δ1.25-1.45 (m, 2 H), 1.70-1.95 (m, 2 H),2.50-2.85 (m, 5 H), 3.54 (brd, J=12.4 Hz, 2 H), 3.65-3.95 (m, 3 H),6.60-6.90 (m, 8 H), 7.92 (d, J=1.6 Hz, 1 H), 8.41 (d, J=8.3 Hz, 1 H),8.48 (d, J=1.6 Hz, 1 H), 8.61 (dd, J=8.3, 2.0 Hz, 1 H), 8.89 (s, 1 H),9.23 (s, 1 H); MS (ES) m/z: 713.1 (MH⁺); HRMS Calcd. for C₃₀H₃₂F₃N₄O₇S₃(MH⁺): 713.1385. Found: 713.1407.

EXAMPLE 3014-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-benzenesulfonamide

[0659] The title compound was prepared from4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 231) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 278 as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.60 (m, 2 H),1.90-2.10 (m, 2 H), 2.50-2.70 (m, 2 H), 2.70-3.50 (m, 5 H), 3.60 (brd,J=11.6 Hz, 2 H), 4.00 (brs, 3 H), 4.60 (dd, J=9.4, 4.2 Hz, 1 H), 6.58(d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.70-6.90 (m, 5 H), 7.35(d, J=8.4 Hz, 2 H), 7.55 (d, J=8.4 Hz, 2 H), 9.70 (brs, 1 H), 10.61(brs, 1 H), 10.72 (brs, 1 H); MS (ES) m/z: 667.0 (MH⁺); HRMS Calcd. forC₃₁H₃₅N₆O₇S₂ (MH⁺): 677.2009. Found: 677.1999.

EXAMPLE 3024-[(2,4-Dioxo-1,3-thiazolidin-5-yl)methyl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide

[0660] The title compound was prepared from4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 9) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.45-1.60 (m, 2H), 1.85-2.05 (m, 2 H), 2.50-3.50 (m, 7 H), 2.93 (s, 3 H), 3.59 (brd,J=11.9 Hz, 2 H), 4.28 (dd, J=7.0, 3.8 Hz, 1 H), 4.60-4.65 (m, 1 H),6.70-6.90 (m, 5 H), 7.05 (dd, J=8.3, 1.9 Hz, 1 H), 7.21 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.3 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H); MS (ES) m/z: 690.0(MH⁺); HRMS Calcd. for C₃₀H₃₆N₅O₈S₃ (MH⁺): 690.1726. Found: 690.1714.

EXAMPLE 303N-{4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]-propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide

[0661] The title compound was prepared from3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 242) and5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Example 12) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.80-1.95 (m, 2 H), 2.39 (t, J=7.2 Hz, 2 H), 2.50-2.75 (m, 5 H), 2.82(t, J=7.2 Hz, 2 H), 3.45-3.55 (m, 2 H), 3.63 (s, 3 H), 3.72(s, 3 H),3.70-3.85 (m, 3 H), 4.91 (brs, 1 H), 6.44 (d, J=8.8 Hz, 1 H), 6.60 (d,J=8.8 Hz, 1 H), 6.78 (d, J=9.1 Hz, 1 H), 6.88 (d, J=9.1 Hz, 1 H), 7.02(d, J=8.5 Hz, 1 H), 7.18 (dd, J=8.5, 2.1 Hz, 1 H), 7.36 (d, J=2.1 Hz, 1H), 8.72 (s, 1 H), 9.17 (brs, 1 H); MS (ES) m/z: 627.1 (MH⁺); HRMSCalcd. for C₃₁H₃₉N₄O₈S (MH⁺): 627.2489. Found: 627.2458.

EXAMPLE 304N-[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-1-octanesulfonamide

[0662] The title compound was prepared from octane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example230) and 4-((2S)-3-amino-2-hydroxy-propoxyl)-phenol (which was obtainedin Example 5) according to the procedure of Example 278 as an off-whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ0.85(t, J=7.0 Hz, 3 H), 1.15-1.45 (m,12 ), 1.50-1.70 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.80 (m, 5 H), 2.92(brt, J=6.7 Hz, 2 H), 3.54 (brd, J=12.3 Hz, 2 H), 3.70-3.90 (m, 3 H),6.66 (d, J=6.7 Hz, 2 H), 6.75 (d, J=8.3 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2 H), 8.89 (brs, 1 H), 9.28 (brs, 1 H); MS (ES)m/z: 534.1 (MH⁺); HRMS Calcd. for C₂₈H₄₄N₃O₅S (MH⁺): 534.3002. Found:534.3017.

EXAMPLE 3054-{[(Hexylamino)carbonyl]amino}-N-{4-[4-(}(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0663] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzensulfonamide(which was obtained in Example 225) and5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Example 12) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=5.1 Hz, 3H), 1.20-1.35 (m, 8 H), 1.35-1.50 (m, 2 H), 1.75-1.90 (m, 2 H), 2.39 (t,J=5.1 Hz, 2 H), 2.50-2.75 (m, 5 H), 2.82 (t, J=5.1 Hz, 2 H), 3.05 (q,J=5.1 Hz, 2 H), 3.40-3.55 (m, 2 H), 3.75-3.85 (m, 3 H), 4.90 (brs, 1 H),6.30 (t, J=5.1 Hz, 1 H), 6.44 (d, J=6.6 Hz, 1 H), 6.59 (d, J=6.6 Hz, 1H), 6.76 (d, J=6.9 Hz, 1 H), 6.85 (d, J=6.9 Hz, 1 H), 7.46 (d, J=6.9 Hz,2 H), 7.50 (d, J=6.9 Hz, 2 H), 8.67 (s, 1 H), 8.84 (s, 1 H), 9.10 (brs,1 H), 9.50 (brs, 1 H); MS (ES) m/z: 709.2 (MH⁺); HRMS Calcd. forC₃₆H₄₉N₆O₇S (MH⁺): 709.3383. Found: 709.3391.

EXAMPLE 306N-{4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]-propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide

[0664] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) and5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Example 12) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.82 (t, J=7.3 Hz, 3H), 1.20-1.40 (m, 4 H), 1.50-1.70 (m, 2 H), 1.80-1.95 (m, 2 H), 2.39 (t,J=7.3 Hz, 2 H), 2.50-2.80 (m, 5 H), 2.85 (t, J=7.3 Hz, 2 H), 2.85-3.00(m, 2 H), 3.45-3.60 (m, 2 H), 3.75-3.85 (m, 3 H), 6.44 (d, J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1 H), 6.89 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz,2 H), 8.74 (s, 1 H); MS (ES) m/z: 546.9 (MH⁺); HRMS Calcd. forC₂₇H₃₉N₄O₆S (MH⁺): 547.2590. Found: 547.2583.

EXAMPLE 307N-[4-({4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolin)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide

[0665] The title compound was prepared fromN-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (whichwas obtained in Example 216) and5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Example 12) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.75-1.90 (m, 2 H), 2.05 (s, 3 H), 2.39 (t, J=7.5 Hz, 2 H), 2.50 2.80(m, 5 H), 2.83 (t, J=7.5 Hz, 2 H), 3.40-3.55 (m, 2 H), 3.70-3.85 (m, 3H), 6.44 (d, J=8.7 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 6.76 (d, J=9.0 Hz,2 H), 6.85 (d, J=9.0 Hz, 2 H), 7.58 (d, J=9.0 Hz, 2 H), 7.67 (d, J=9.0Hz, 2 H), 8.72 (s, 1 H), 10.27 (s, 1 H); MS (ES) m/z: 623.9 (MH⁺); HRMSCalcd. for C₃₁H₃₈N₅O₇S (MH⁺): 624.2492. Found: 624.2469.

EXAMPLE 308N-(4{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)-amino]-1-piperidinyl}phenyl)-4-dimethoxybenzenesulfonamide

[0666] The title compound was prepared from3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide(which was obtained in Example 242) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 14) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-₆) δ1.20-1.40 (m, 2 H),1.75-1.90 (m, 2 H), 2.50-2.80 (m, 5 H), 2.92 (s, 3 H), 3.40-3.55 (m, 2H), 3.71 (s, 3 H), 3.78 (s, 3 H), 3.70-3.85 (m, 3 H), 6.60 (dd, J=8.8,2.9 Hz, 1 H), 6.706.85 (m, 5 H), 6.88 (d, J,=9.0 Hz, 2 H), 7.02 (d,J=8.6 Hz, 2 H), 7.16 (d, J=2.1 Hz, 1 H), 7.23 (dd, J=8.4, 2.1 Hz, 1 H);MS (ES) m/z: 650.9 (MH⁺); HRMS Calcd. for C₂₉H₃₉N₄O₉S₂ (MH⁺): 651.2158Found: 651.2117.

EXAMPLE 309N-(4-{4-[((2S)-2-Hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}-propyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide

[0667] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 14) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆δ0.83 (t, J=7.3 Hz, 3H), 1.25-1.40 (m, 2 H), 1.55-1.70 (m, 2 H), 1.80-1.95 (m, 2 H),2.50-2.80 (m, 5 H), 2.92 (s, 3 H), 2.85-3.30 (m, 2 H), 3.50-3.65 (m, 2H), 3.70-3.90 (m, 3 H), 6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.70-6.80 (m, 2H), 6.88 (d, J=8.9 Hz, 2 H), 7.05 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 571.0(MH⁺); HRMS Calcd. for C₂₅H₃₉N₄O₇S₂ (MH⁺): 571.2261. Found: 571.2279.

EXAMPLE 3104-{[(Hexylamino)carbonyl]amino}-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}benzenesulfonamide

[0668] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benezensulfonamide(which was obtained in Example 225) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 14) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=6.9 Hz,3 H), 1.25-1.40 (m, 8 H), 1.30-1.45 (m, 2 H), 1.75-1.90 (m, 2 H),2.50-2.75 (m, 5 H), 2.92 (s, 3 H), 3.00-3.15 (m, 2 H), 3.45-3.55 (m, 2H), 3.70-3.90 (m, 3 H), 6.32 (t, J=5.6 Hz, 1 H), 6.60 (dd, J=8.8, 2.9Hz, 1 H), 6.70-6.80 (m, 4 H), 6.85 (d, J=9.1 Hz, 2 H), 7.45 (d, J=6.8Hz, 2 H), 7.50 (d, J=6.8 Hz, 2 H), 8.64 (brs, 1 H); MS (ES) m/z: 733.1(MH⁺); HRMS Calcd. for C₃₄H₄₉N₆O₈S₂ (MH⁺): 733.3053. Found: 733.3049.

EXAMPLE 311N-[4-(4-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino-}-piperdinyl)phenyl]-4-}[(hexylamino)carbonyl]amino}benzenesulfonamide

[0669] The title compound was prepared from4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]benzensulfonamide(which was obtained in Example 225) and(1)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example1according to the procedure of Example 278 as a brown solid; ¹H NMR (300MHz, DMSO-d ₆) δ0.84 (t, J=6.9 Hz, 3 H), 1.20-1.50 (m, 10 H), 1.75-1.90(m, 2 H), 2.50-2.80 (m, 5 H), 3.00-3.15 (m, 2 H), 3.40-3.50 (m, 2 H),4.60 (dd, J=8.1, 3.8 Hz, 1 H), 6.29 (t, J=5.7 Hz, 1 H), 6.77 (d, J=9.1Hz, 2 H), 6.85 (d, J=9.1 Hz, 2 H), 7.25-7.50 (m, 8 H), 8.94 (s, 1 H),9.55 (brs, 1 H); MS (ES) m/z: 628.1 (MH⁺); HRMS Calcd. for C₃₂H₄₃ClN₅O₄S(MH⁺): 628.2748. Found: 628.2718.

EXAMPLE 312Ethyl{4-[(4-}4-[((2S)-2hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]-phenoxy{propyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetate

[0670] The title compound was prepared from{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetic acid methylester (which was prepared according to the procedure of Example 225) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 14) according to the procedure of Example278 as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.16 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2 H), 1.75-1.90 (m, 2 H), 2.50-2.80 (m, 5 H), 2.91 (s,3 H), 3.40-3.55 (m, 2 H), 3.74 (s, 2 H), 3.70-3.85 (m, 3 H), 4.07 (q,J=7.1 Hz, 2 H), 6.59 (dd, J=8.8, 3.0 Hz, 1 H), 6.70-6.80 (m, 4 H), 6.87(d, J=9.1 Hz, 2 H), 7.41 (d, J=8.4 Hz, 2 H), 7.63 (d, J=8.4 Hz, 2 H); MS(ES) m/z: 677.0 (MH⁺); Calcd. for C₃₁H₄₁N₄O₉S₂ (MH⁺): 677.2315. Found:677.2289.

EXAMPLE 313Methyl{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1piperidinyl{anilino)sulfonyl]phenoxy{acetate

[0671] The title compound was prepared from{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acidmethyl ester (which was obtained in Example 232) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (whichwas obtained in Example 10) according to the procedure of Example 278 asan off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.75-1.90 (m, 2 H), 2.50-2.80 (m, 5 H), 2.92 (s, 3 H), 3.65-3.75 (m, 2H), 3.67 (s, 3 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 4.87 (s, 2 H),6.50-6.90 )m, 8 H), 7.17 (d, J=1.8 Hz, 1 H), 7.59 (d, J=8.9 Hz, 2 H); MS(ES) m/z: 649.0 (MH⁺); HRMS Calcd. for C₂₉H₃₇N₄O₉S₂ (MH⁺): 649.2004.Found: 649.2014.

EXAMPLE 314Methyl[4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenoxy]acetate

[0672] The title compound was prepared from{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acidmethyl ester (which was obtained in Example 232) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat No. 5,786,356/1998) according to the procedure of Example 278 as apale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.75-1.90 (m, 2 H), 2.50-2.85 (m, 5 H), 3.30-3.50 (m, 2 H), 3.69 (s, 3H), 3.80-4.05 (m, 3 H), 4.87 (s, 2 H), 6.56 (d, J=7.8 Hz, 1 H), 6.61 (d,J=8.1 Hz, 1 H), 6.65-6.90 (m, 5 H), 7.02 (d, J=9.0 Hz, 2 H), 7.59 (d,J=9.0 Hz, 2H), 10.60 (s, 1 H), 10.75 (brs, 1 H); MS (ES) m/z: 626.1(MH⁺); HRMS Calcd. for C₃₀H₃₆N₅O₈S (MH⁺): 626.2285. Found: 626.2298.

EXAMPLE 315N-[5-({(2S)-3-[(1-{4-[(Butylsulfonyl)amino]phenyl}-4-piperidinyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]benzenesulfonamide

[0673] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide(which was obtained in Example 21) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.83 (t, J=7.3 Hz,3 H), 1.20-1.40 (m, 4 H), 1.55-1.70 (m, 2 H), 1.80-1.95 (m, 2 H),2.50-2.80 (m, 5 H), 2.92 (t, J=7.6 Hz, 2 H), 3.50-3.90 (m, 5 H), 6.39(d, J=8.7, 2.9 Hz, 1 H), 6.57 (d, J=8.7 Hz, 1 H), 6.72 (d, J=2.9 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 7.05 (d, J=9.0 Hz, 2 H), 7.40-7.60 (m, 3 H),7.74 (d, J=7.7 Hz, 2 H); MS (ES) m/z: 633.1 (MH⁺); HRMS Calcd. forC₃₀H₄₁N₄O₇S₂ (MH⁺): 633.2411. Found: 633.2409.

EXAMPLE 316N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(isopropylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide

[0674] The title compound was prepared from butane-1-sulfonic acid[4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example228) and propane-2-sulfonic acid[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide (which wasobtained in Example 27) according to the procedure of Example 278 as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.83 (t, J=7.3 Hz, 3 H),1.20-1.40 (m, 4 H), 1.25 (d, J=6.8 Hz, 6 H), 1.55-1.75 (m, 2 H),1.75-1.90 (m, 2 H), 2.50-2.75 (m, 5 H), 2.92 (t, J=7.7 Hz, 2 H),3.05-3.15 (m, 1 H), 3.45-3.60 (m, 2 H), 4.46 (dd, J=7.8, 4.5 Hz, 1 H),6.78 (d, J=8.2 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2 H), 6.96 (dd, J=8.2, 2.0Hz, 1H), 7.04 (d, J=9.0 Hz, 2 H), 7.23 (d, J=2.0 Hz, 1 H); MS (ES) m/z:569.0 (MH⁺); HRMS Calcd. for C₂₆H₄₁N₄O₆S₂ (MH⁺): 569.2462. Found:569.2458.

EXAMPLE 3174-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]benzoicacid

[0675] The title compound was prepared from4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid (which wasobtained in Example 233) andN-[5-((1R)-2amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.35-1.50 (m, 2 H),1.75-2.00 (m, 2 H), 2.50-2.95 (m, 5 H), 2.92 (s, 3 H), 3.45-3.60 (m, 2H), 4.60-4.70 (m, 1 H), 6.77 (d, J=9.3 Hz, 2 H), 6.80-6.90 (m, 3 H),7.02 (dd, J=8.4, 1.8 Hz, 1 H), 7.20 (d, J=1.8 Hz, 1 H), 7.60 (d, J=8.4Hz, 2H), 7.93 (d, J=8.4 Hz, 2 H); MS (ES) m/z: 603.2 (M−H)⁻; HRMS Calcd.for C₂₇H₃₁N₄O₈S₂ (M−H)⁻: 603:1588. Found: 603.1572.

EXAMPLE 318Ethyl4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)-amino]-1-piperidinyl}anilino)sulfonyl]benzoate

[0676] The title compound was prepared from4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid ethyl ester(which was obtained in Example 235) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as a pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m,2 H), 1.32 (t, J=7.1 Hz, 3 H), 1.75-1.90 (m, 2 H), 2.50-2.70 (m, 5 H),2.91 (s, 3 H), 3.40-3.55 (m, 2 H), 4.32 (q, J=7.1 Hz, 2 H), 4.47 (dd,J=8.1, 4.2 Hz, 1 H), 6.70-6.90 (m, 5 H), 6.99 (dd, J=8.3, 2.0 Hz, 1 H),7.17 (d, J=2.0 Hz, 1 H), 7.79 (d, J=8.5 Hz, 2 H), 8.07 (d, J=8.5 Hz, 2H); MS (ES) m/z: 633.3 (MH⁺); HRMS Calcd. for C₂₉H₃₇N₄O₈S₂ (MH⁺):633.2047. Found: 633.2013.

EXAMPLE 319Methyl{4-[(4-{4-[((2R)-2-{4-chloro-3-[(methylsulfonyl)amino]phenyl}-2-hydroxyethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenoxy}acetate

[0677] The title compound was prepared from{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}acetic acid methylester (which was obtained in Example 232) andN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-chloro-phenyl]-methanesulfonamide(which was obtained in Example 25) according to the procedure of Example95 as a pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.75-1.90 (m, 2 H), 2.50-2.80 (m, 5 H), 2.97 (s, 3 H), 3.40-3.55 (m, 2H), 3.69 (s, 3 H), 4.63 (dd, J=8.0; 3.8 Hz, 1 H), 4.87(s, 2 H), 6.77 (d,J=9.0 Hz, 2 H), 6.87 (d, J=9.0 Hz, 2 H), 7.03 (d, J=9.0 Hz, 2 H), 7.17(dd, J=8.3, 1.7 Hz, 1 H), 7.43 (d, J=8.3 Hz, 1 H), 7.43 (d, J=1.7 Hz, 1H), 7.62 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 667.0 (MH⁺); HRMS Calcd. forC₂₉H₃₆ClN₄O₈S₂ (MH⁺): 667.1657. Found: 667.1651.

EXAMPLE 320Methyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylate

[0678] The title compound was prepared from3-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-thiopene-2-carboxylic acidmethyl ester (which was obtained in Example 234) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (whichwas obtained in Example 10) according to the procedure of Example 278 asa pale yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.70-1.90 (m, 2 H), 2.50-2.75 (m, 5 H), 3.40-3.55 (m, 2 H), 3.89 (s, 2H), 4.46 (dd, J=8.0, 4.2 Hz, 1 H), 6.75-6.85(m, 3 H), 6.90 (d, J=9.0 Hz,2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.16 (d, J=2.0 Hz, 1 H), 7.32 (d,J=3.3 Hz, 1 H), 7.89 (d, J=3.3 Hz, 1 H); MS (ES) m/z: 624.9 (MH⁺); HRMSCalcd. for C₂₆H₃₄N₄O₈S₃ (MH⁺): 625.1455. Found: 625.1441.

EXAMPLE 3213-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylicacid

[0679] The title compound was prepared from methyl3-[(4-(4-[((2R)-2-hydroxy-2-}4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylate(which was obtained in Example 320) by NaOH hydrolysis as a pale greysolid; ¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.70 (m, 2 H), 1.95-2.10 (m, 2H), 2.50-2.70 (m, 2 H), 2.95 (s, 3 H), 3.00-3.30 (m, 3 H), 3.60-3.70 (m,2 H), 4.75-4.85 (m, 1 H), 6.10 (brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H),6.85-6.95(m, 3 H) 7.04 (d, J=5.4 Hz, 1 H), 7.08 (dd, J=8.4, 1.8 Hz, 1H), 7.26 (d, J=1.8 Hz, 1 H), 7.39 (d, J=5.4 Hz, 1 H), 8.73 (brs, 1 H),9.96 (brs, 1 H); MS (ES) m/z: 610.7 (MH⁺); HRMS Calcd. for C₂₅H₃₁N₄O₈S₃(MH⁺): 611.1299. Found: 611.1284.

EXAMPLE 322Benzyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)sulfonyl]acetate

[0680] The title compound was prepared from[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic acid benzyl ester(which was obtained in Example 236) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H),1.70-1.95 (m, 2 H), 2.50-2.75 (m, 2 H), 2.92 (s, 3 H), 3.50-3.60 (m, 3H), 4.13 (s, 2 H), 4.48 (dd, J=8.0, 4.3 Hz, 1 H), 5.15 (s, 2 H) 6.82 (d,J=8.3 Hz, 1 H), 6.86 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H),7.06 (d, J=9.0 Hz, 2H),7.18 (d, J=2.0Hz, 1 H), 7.30-7.40 (m, 5 H); MS(ES) m/z: 633.3 (MH⁺); HRMS Calcd. for C₂₉H₃₇N₄O₈S₂ (MH⁺): 633.2047.Found: 633.2031.

EXAMPLE 323[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid

[0681] The title compound was prepared from[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic acid benzyl ester(which was obtained in Example 236) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example255 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.60 (m, 2H), 1.90-2.05 (m, 2 H), 2.50-2.90 (m, 5 H), 2.94 (s, 3 H), 3.50-3.65 (m,2 H), 4.65-4.75 (m, 1 H), 6.80-6.90 (m, 3 H), 7.00-7.10 (m, 3 H), 7.23(d, J=2.0 Hz, 1 H); MS (ES) m/z: 543.3 (MH⁺); HRMS Calcd. forC₂₉H₃₇N₄O₈S₂(MH⁺): 543.1578. Found: 543.1572.

EXAMPLE 324Benzyl[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl)anilino)sulfonyl}acetate

[0682] The title compound was prepared from benzyl{[butyl-4-(4-oxo-1-piperidinyl}anilino]sulfonyl]acetate (which wasobtained in Example 253) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) d 0.79(t, J=7.2 Hz,3 H), 1.10-1.40 (m, 6 H), 1.80-1.95 (m, 2 H), 2.55-2.80 (m, 5 H), 2.92(s, 3 H), 3.45 (t, J=7.1 Hz, 2 H), 4.24 (s, 2 H), 4.49(dd, J=7.9, 4.2Hz, 1 H), 5.20 (s, 2 H), 6.82 (d, J=8.2 Hz, 1 H), 6.92 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.10-7.20 (m, 3 H), 7.30-7.45 (m, 5H); MS (ES) m/z: 689.1 (MH⁺); HRMS Calcd. for C₃₃H₄₅N₄O₈S₂ (MH⁺):689.2673. Found: 689.2679.

EXAMPLE 325[(Butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid

[0683] The title compound was prepared from benzyl{[butyl-4-(4-oxo-1-piperidinyl) anilino]sulfonyl}acetate (which wasobtained in Example 253) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (whichwas obtained in Example 10) according to the procedure of Example 255 asa pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.79(t, J=7.1 Hz, 3 H),1.10-1.35 (m, 4 H), 1.50-1.70 (m, 2 H), 2.00-2.10 (m, 2 H), 2.55-3.10(m, 5 H), 2.92(s,3 H), 3.55-3.70 (m, 2 H), 3.70-3.85 (m, 2 H), 4.75-4.85(m, 1 H), 6.88 (d, J=8.3 Hz, 1 H), 6.92 (d, J=9.0 Hz, 2 H), 7.08 (dd,J=8.3, 2.0 Hz, 1 H), 7.20-7.35 (m, 3 H); MS (ES) m/z: 597.1 (M−H)⁻; HRMSCalcd. for C₂₆H₃₉N₄O₈S₂ (MH⁺): 599.2204. Found: 599.2218.

EXAMPLE 326N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3-pyridinesulfonamide

[0684] To a stirred mixture of pyridine-3-sulfonic acid-[4-(4-oxopiperidin-1-yl)-phenyl]amide (which was obtained in Example 237) (0.94g, 2.8 mmol),N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) (0.70 g, 2.8 mmol) indimethylformamide (10 mL) at room temperature was added sodiumtriacetoxyborohydride (0.72 g, 3.4 mmol) and glacial acid (0.18 mL, 3.1mmol). The reaction was stirred under N₂ atmosphere for 18 hours. Thereaction mixture was poured onto 1:1 water/saturated sodium bicarbonate,extracted with ethyl acetate three times, dried over sodium sulfate andconcentrated. The product was purified by flash silica gelchromatography eluting with 10% methanol in methylene chloride andfinally with 20% methanol in methylene chloride to give the titledcompound as a yellow solid (0.23 g, 15%); ¹H NMR (300 MHz, DMSO-d₆)δ1.25-1.45 (m, 2 H), 1.80-1.95(m, 2 H), 2.50-2.80(m, 5 H), 2.92(s, 3 H),3.40-3.55(m, 2), 4.45-4.60(m, 1 H), 6.85-6.90(m, 5 H), 7.02(dd, J=8.3,2.0 Hz, 1 H), 7.18(d, J=2.0 Hz, 1 H), 7.59(dd, J=7.4, 4.4 Hz, 1 H),7.95-8.05(m, 2 H), 8.70-8.80(m, 2 H); MS (ES) m/z: 561.95 (MH⁺, 100%);HRMS Calcd. for C₂₅H₃₂N₅O₆S₂(MH⁺): 562.1788. Found: 562.1774.

EXAMPLE 3273,4-Dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0685] The title compound was prepared according to the procedure ofExample 326 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.29-1.41 (m,2H), 1.87-1.91 (m, 2H), 2.60-2.75 (m, 5H), 2.82-2.93 (m, 1H), 3.53-3.57(m, 2H), 3.88-4.04 (m, 4H), 4.99 (brs, 1H), 6.55-6.63 (m, 2H), 6.79-6.89(m, 5H), 7.55-7.60 (m, 1H), 7.81-7.95 (m, 2H), 10.58 (s, 1H), 10.70(brs, 1H); MS (ES) m/z: 605.9 (MH⁺); HRMS found for C₂₇H₂₉Cl₂N₅O₅S:606.1323.

EXAMPLE 328N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino-1-piperidinyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide

[0686] The title compound was prepared according to the procedure ofExample 326 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.33-1.37 (m,2H), 1.87-1.90 (m, 2H), 2.59-2.69 (m, 4H), 2.72-2.76 (m, 1H), 2.84-2.96(m, 1H), 3.47-3.56 (m, 2H), 3.92-4.04 (m, 4H), 5.01 (brs, 1H), 6.55-6.63(m, 2H), 6.78-6.94 (m, 5H), 7.87 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz,2H), 10.5 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 606.1 (MH⁺); HRMS foundfor C₂₈H₃₀F₃N₅O₅S; 606.1989.

EXAMPLE 329N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-4-(trifluoromethoxy)benzenesulfonamide

[0687] The title compound was prepared according to the procedure ofExample 326 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.32-1.36 (m,2H), 1.86-1.90 (m, 2H), 2.58-2.73 (m, 6H), 2.81-2.89 (m, 1H), 3.51-3.55(m, 2H), 3.91-3.96 (m, 2H), 3.99-4.04 (m, 1H), 4.95 (brs, 1H), 6.55-6.63(m, 2H), 6.78-6.89 (m, 5H), 7.54 (d, J=8.1 Hz, 2H), 7.76-7.82 (m, 2H),10.5 (s, 1H), 10.65 (brs, 1H); MS (ES) m/z: 622.0 (MH⁺); HRMS found forC₂₈H₃₀F₃N₅O₆S: 622.1961.

EXAMPLE 330N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-4-methoxybenzenesulfonamide

[0688] The title compound was prepared according to the procedure ofExample 326 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.23-1.36 (m,2H), 1.84-1.88 (m, 2H), 2.57-2.73 (m, 6H), 2.76-2.82 (m, 1H), 3.48-3.52(m, 2H), 3.79 (s, 3H), 3.87-3.95 (m, 2H), 3.99-4.04 (m, 1H), 4.90 (brs,1H), 6.55-6.63 (m, 2H); 6.75-6.88 (m, 5H), 7.00-7.05 (m, 2H), 7.57-7.68(m, 2H), 10.65 (s, 1H), 10.8 (brs, 1H); MS (ES) m/z: 568.1 (MH⁺); HRMSfound for C₂₈H₃₃N₅O₆S: 568.220.

EXAMPLE 3314-Chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0689] The title compound was prepared according to the procedure ofExample 326 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.23-1.39 (m,2H), 1.90-1.99 (m, 2H), 2.59-2.73 (m, 6H), 2.81-2.86 (m, 1H), 3.46-3.55(m, 2H), 3.99-4.04 (m, 2H), 4.07-4.13 (m, 1H), 4.95 (brs, 1H), 6.55-6.62(m, 2H), 6.67-6.92 (m, 5H), 7.59-7.68 (m, 4H), 10.6 (s, 1H), 10.7 (brs,1H); MS (ES) m/z: 571.9 (MH⁺); HRMS found for C₂₇H₃₀ClN₅O₅S: 572.1750.

EXAMPLE 3324-Butyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy[propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide.

[0690] The title compound was prepared according to the procedure ofExample 326 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.87 (t,J=7.23 Hz, 3H), 1.22-1.35 (m, 4H), 1.47-1.58 (m, 2H), 1.86-1.90 (m, 2H),2.60-2.65 (m, 6H), 2.71-2.72 (m, 2H), 2.73-2.85 (m, 1H), 3.49-3.53 (m,2H), 3.91-3.99 (m, 1H), 4.01-4.12 (m, 2H), 4.95 (brs, 1H), 6.55-6.63 (m,2H), 6.75-6.89 (m, 5H), 7.33 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H),10.58 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 594.1 (MH⁺); HRMS found forC₃₁H₃₉N₅O₅S: 594.2674.

EXAMPLE 3333,5-Dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0691] The title compound was prepared according to the procedure ofExample 326 as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.29-1.40 (m,2H), 1.87-1.91 (m, 2H), 2.61-2.75 (m, 4H), 2.84-2.88 (m, 2H), 3.46-3.58(m, 2H), 3.92-3.97 (m, 2H), 3.99-4.04 (m, 2H), 4.99 (brs, 1H), 6.55-6.63(m, 2H), 6.80-6.94 (m, 5H), 7.6 (d, J=1.8 Hz, 2H), 7.93 (t, J=1.8 Hz,1H), 10.58 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 606.0 (MH⁺); HRMS foundfor C₂₇H₂₉Cl₂N₅O₅S: 606.1291.

EXAMPLE 334N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-2,5-dimethoxybenzenesulfonamide

[0692] The title compound was prepared according to the procedure ofExample 326 as a yellow solid, ¹H NMR (300 MHz, DMSO-d₆) δ1.23-1.40 (m,2H), 1.91 (m, 2H), 2.55-2.63 (m, 4H), 2.72-2.73 (m, 1H), 2.82 (m, 1H),3.44-3.52 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 3.91-4.04 (m, 4H), 4.87(brs, 1H), 6.55-6.62 (m, 2H), 6.67-6.92 (m, 5H), 7.12-7.13 (m, 3H),10.57 (s, 1H), 10.69 (brs, 1H); MS (ES) m/z: 598.1 (MH⁺); HRMS found forC₂₉H₃₅N₅O₇S: 598.2343.

EXAMPLE 335N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2,5-dimethoxybenzenesulfonamide

[0693] The title compound was prepared according to the procedure ofExample 326 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.34-1.37 (m,2H), 1.84-1.90 (m, 2H), 2.53-2.66 (m, 2H), 2.69-2.75 (m, 3H), 2.92 (s,3H), 3.01-3.08 (m, 2H), 3.49-3.53 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H),4.55-4.57 (m, 2H), 5.4 (brs, 1H), 6.53 (d, J=7.8 Hz, 2H), 6.70-6.92 (m,3H), 6.99-7.04 (m, 2H), 7.12 (d, J=2.61 Hz, 2H), 7.19 (d, J=1.92 Hz,1H), 9.44 (brs, 1H); MS (ES) m/z: 621.0 (MH⁺); HRMS found forC₂₈H₃₆N₄O₈S₂: 621.2049.

EXAMPLE 336Ethyl{[(4-butylphenyl)sulfonyl]-4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}acetate

[0694] The title compound was prepared according to the procedure ofExample 326 as an off-white solid; 1H NMR (300 MHz, DMSO-d₆) δ0.89 (t,J=7.26 Hz, 3H), 1.13 (t, J=7.11 Hz, 3H), 1.23-1.36 (m, 4H), 1.48-1.62(m, 2H), 1.86-1.90 (m, 2H), 2.26-2.28 (m, 2H), 2.58 (m, 1H), 2.63-2.71(m, 4H), 2.74-2.79 (m, 1H), 3.60-3.71 (m, 2H), 3.88-3.96 (m, 2H),4.00-4.13 (m, 3H), 4.39 (s, 2H), 4.90 (brs, 1H), 6.59 (q, J=7.59 Hz,2H), 6.79-6.93 (m, 5H), 7.38 (d, J=8.31 Hz, 2H), 7.54 (d, J=8.31 Hz,2H), 10.6 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 680.2 (MH⁺); HRMS foundfor C₃₅H₄₅N₅O₇S: 680.3112.

EXAMPLE 3375-Bromo-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-N-{4-[4-({2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide

[0695] The title compound was prepared according to the procedure ofExample 326 as a dull yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.23-1.35(m, 2H), 1.90 (m, 2H), 2.27-2.28 (m, 2H), 2.57-2.73 (m, 2H), 2.79-2.86(m, 2H), 3.49 (s, 3H), 3.71 (s, 3H), 3.91-3.96 (m, 2H), 4.01-4.06 (m,2H), 4.13-4.15 (m, 1H), 4.91 (brs, 1H), 6.55-6.64 (m, 2H), 6.82-7.00 (m,8H), 7.20 (d, J=9.09 Hz, 1H), 7.60 (d, J=2.55 Hz, 1H), 7.88 (dd, J=2.52Hz, 6.39 Hz, 1H), 10.6 (s, 1H), 10.7 (brs, 1H); MS (ES) m/z: 896.0(MH⁺); HRMS found for C₃₅H₃₇Br₂N₅O₉S₂: 896.0486.

EXAMPLE 3385-Bromo-N-{4-[4-(f{(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide

[0696] The title compound was prepared according tothe procedure ofExample 326 as a moss green solid; 1H NMR (300 MHz, DMSO-d₆) δ1.23-1.37(m, 2H), 1.84-1.90 (m, 2H), 2.57-2.65 (m, 2H), 2.69-2.73 (m, 2H),2.80-2.83 (m, 1H), 3.49-3.53 (m, 2H), 3.91 (s, 3H), 3.86-3.96 (m, 2H),3.99-4.04 (m, 2H), 4.09-4.15 (m, 1H), 4.95 (brs, 1H), 6.55-6.63 (m, 2H),6.75-6.91 (m, 5H), 7.17 (d, J=8.94 Hz, 1H), 7.66 (d, J=2.58 Hz, 1H),7.73 (dd, J=2.55 Hz, 6.24 Hz, 1H), 10.55 (s, 1H), 10.65 (brs, 1H); MS(ES) m/z: 647.9 (MH⁺); HRMS found for C₂₈H₃₂BrN₅O₆S: 646.1331.

EXAMPLE 339Ethyl([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate

[0697] The title compound was prepared according to the procedure ofExample 326 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.14 (t,J=7.08 Hz, 3H), 1.24-1.33 (m, 2H), 1.81-1.91 (m, 2H), 2.26-2.28 (m, 2H),2.60-2.73 (m, 4H), 2.92 (s, 1H), 3.17 (s, 1H), 3.61-3.65 (m, 3H), 3.72(s, 3H), 3.83 (m, 3H), 4.06 (q, J=7.11 Hz, 2H), 4.38 (s, 3H), 4.48-4.52(m, 2H), 5.76 (s, 1H), 6.81-6.85 (m, 2H), 6.91-6.95 (m, 2H), 7.00 (d,J=2.01 Hz, 1H), 7.03 (d, J=2.01 Hz, 2H), 7.07 (s, 1H), 7.10 (s, 1H),7.18 (d, J=2.01 Hz, 1H), 7.21(d, J=2.1 Hz, 1H); MS (ES) m/z: 707.0(MH⁺); HRMS found for C₃₂H₄₂N₄O₁₀S₂: 707.2418.

EXAMPLE 340Ethyl5-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-1H-indole-3-carboxylate

[0698] The title compound was prepared according to the procedure ofExample 326 as an off-white solid; 1H NMR (300 MHz, DMSO-d₆) δ1.23 (m,2H), 1.33 (t, J=7.08 Hz, 3H), 1.84-191 (m, 2H), 2.58-2.66 (m, 3H), 2.61(s, 3H), 2.72-2.89 (m, 2H), 3.47-3.53 (m, 2H), 3.71 (s, 3H), 3.78 (m,3H), 3.87-3.96 (m, 4H), 4.22 (q, J=7.08 Hz, 2H), 5.12 (brs, 3H),6.74-.82 (m, 3H), 6.88 (d, J=9.0 Hz, 2H), 7.02 (d, J=8.7 Hz, 1H), 7.16(d, J=2.1 Hz, 1H), 1H), 7.20-7.27 (m, 2H), 7.43 (d, J=2.4 Hz, 1H), 9.62(brs, 1H), 11.67 (s, 1H); MS, (ES) m/z: 667.1 (MH⁺); HRMS found forC₃₄H₄₂N₄O₈S: 667.2797.

EXAMPLE 341 Ethyl4-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate

[0699] The title compound was prepared according to the procedure ofExample 326 as a light grey solid; 1H NMR,(300 MHz, DMSO-d₆) δ1.27 (t,J=7.11 Hz, 3H), 1.34-1.39 (m, 2H), 1.83-1.91 (m, 2H), 2.42 (s, 3H),2.57-2.69 (m, 4H), 2.72-2.76 (m, 1H), 2.75-2.86 (m, 2H), 3.52-3.63 (m,2H), 3.72 (s, 3H), 3.78 (m, 3H), 3.85-3.91 (m, 2H), 4.18 (q, J=7.11 Hz,2H), 5.76 (s, 1H), 6.79 (d, J=9.09, 2H), 6.89 (d, J=9.03 Hz, 2H), 7.03(d, J=8.52 Hz, 1H), 7.13-7.24 (m, 3H), 7.29-7.38 (m, 2H), 7.76 (d,J=7.47 Hz, 2H), 9.59 (brs, 1H), 11.3 (s, 1H); MS (ES) m/z: 693.1 (MH⁺);HRMS found for C₃₆H₄₄N₄O₈S: 693;2953.

EXAMPLE 342Benzyl((butylsulfonyl)-4-(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-[amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate

[0700] The title compound was prepared according to the procedure ofExample 326 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.85 (t,J=7.35 Hz, 3H), 1.14-1.40 (m, 4H), 1.58-1.69 (m, 4H), 1.83-1.91 (m, 2H),2.60-2.78 (m, 8H), 2.92 (s, 3H), 3.05-3.17 (m, 2H), 3.63-3.67 (m, 2H),4.49 (s, 3H), 5.12 (s, 2H), 5.25 (brs, 1H), 6.83 (d, J=8.22 Hz, 1H),6.90 (d, J=9.06 Hz, 2H), 7.01 (dd, J=1.95 Hz, 8.31 Hz, 2H), 7.18 (d,J=1.95 Hz, 1H), 7.23 (d, J=8.97 Hz, 2H), 7.22-7.39 (m, 4H); MS (ES) m/z:689.1 (MH⁺); HRMS found for C₃₃H₄₄N₄O₈S₂: 689.2669.

EXAMPLE 343((Butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid

[0701] A mixture of 0.18 g of[(butane-1-sulfonyl)-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-amino]-aceticacid benzyl ester (which was obtained in Example 342) and 0.05 g of 10%palladium on carbon in 15 mL of methanol was shaken on a Parrhydrogenator at 25 psi overnight. The mixture was filtered through a padof celite and the filtrate was concentrated in vacuo, which afforded abeige solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.86 (t, J=7.23 Hz, 3H),1.29-1.41 (m, 2H), 1.48-1.51 (m, 2H), 1.54-1.73 (m, 2H), 1.92-2.09 (m,2H), 2.57-2.64 (m, 2H), 2.79-2.87 (m, 2H), 2.94 (s, 3H), 3.00-3.07 (m,4H), 3.16 (s, 2H), 3.20-3.26 (m, 2H), 3.64-3.75 (m, 2H), 4.02-4.04 (m,2H), 4.77-4.81 (m, 1H), 6.84-6.91 (m, 3H), 7.06 (dd, J=2.1 Hz, 8.4 Hz,2H), 7.23 (d, J=1.8 Hz, 1H), 7.34 (d, J=9.00 Hz, 2H); MS (ES) m/z:599.0(MH⁺); HRMS found for C₂₆H₃₈N₄O₈S₂: 599.2

EXAMPLE 344([(3,4-Dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid

[0702] The title compound was prepared according to the procedure ofExample 255 as a grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.48-1.70 (m,4H), 2.02-2.10 (m, 2H), 2.61-2.73 (s, 2H), 2.95 (s, 3H), 3.05-3.09 (m,1H), 3.17 (s, 2H), 3.73 (s, 3H), 3.79 (m, 2H), 3.83 (s, 3H), 4.11 (brs,1H), 4.26 (s, 1H), 4.81-4.84 (m, 1H), 6.19 (brs, 1H), 6.84-6.87 (m, 3H),6.89 (s, 1H), 6.97 (d, J=9.0 Hz, 2H), 7.04-7.10 (m, 2H), 7.20 (dd, J=2.1Hz, 8.4 Hz, 1H), 7.25 (d, J =2.1 Hz, 1H), 8.79 (brs, 1H), 10.17 (brs,1H); MS (ES) m/z: 679.0 (MH⁺); HRMS found for C₃₀H₃₈N₄O₁₀S₂: 679.2126.

EXAMPLE 345 Ethyl((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenylethyl)amino]-1-piperidinyl}anilino)acetate

[0703] The title compound was prepared according to the procedure ofExample 326 as a yellow solid; ¹H NMR (300 MHz, DMSO-d6) δ0.87 (t,J=7.29 Hz, 3H), 1.14-1.20 (m, 4H 1.30-1.43 (m, 4H), 1.60-1.70 (m, 2H),1.84-1.91 (m, 2H), 2.60-2.78 (m, 6H), 3.11-3.16 (m, 2H), 3.32 (brs, 4H),3.63-3.68 (m, 2H), 3.95-4.14 (m, 2H), 4.38 (s, 2H), 4.48-4.53 (m, 1H),5.3 (brs, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.91 (d, J=9.3 Hz, 2H), 7.01 (dd,J=1.8 Hz, 8.1 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.25 (d, J=9.0 Hz, 2H);.MS (ES) m/z: 627.3 (MH⁺); HRMS found for C₂₈H₄₂N₄O₈S₂: 627.2503.

EXAMPLE 3464-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide

[0704] Example 346 illustrated a solution phase combinatorialmethodology for preparing compounds of the present invention in matrixfashion. A 3×3 grid of 20 mL Teflon lined screw cap vials was arranged.To each vial was added the amino ketone, the solvents, and the base,then one sulfonyl chloride per row, one arylethanolamine oraryloxypropanolamine per column, was added according to the followingdetailed procedure: To a suspension of 1-(4-aminophenyl)-4-piperidonehydrochloride (which was obtained in Example 224) (79 mg, 0.3 mmol) in10 mL of THF/CH₂Cl₂ (1:1) was added4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonyl chloride (167mg, 0.45 mmol), triethylamine (0.1 mL), and(piperidinomethyl)polystyrene (462 mg, 2.6 mmol/g). The mixture wasshaken for 1 day. Aminomethylated polystyrene resin (95 mg, 2.6 mmol/g)was added to the reaction along with 1 mL of CH₂Cl₂ and the reaction wascontinued for another day. The resins were removed by filtration andwashed with CH₂Cl₂ (3×1 mL). The filtrate and washings were combined andconcentrated to give4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamidewhich was redissolved in 10 mL of trimethyl orthoformate/methanol (1:1).To the solution was added (2S)-1-amino-3-phenoxy-propan-2-ol (75 mg,0.45 mmol). The mixture was shaken for 18 hours and then AmberliteIRA-400 borohydride resin (360 mg, 2.5 mmol/g) was added to the mixtureand reaction was continued for 5 hours. To the mixture was then addedformylpolystyrene (1 g, 0.5 mmol/g) and 1 mL of CH₂Cl₂. The reaction wascontinued for 18 hours. The resins were removed by filtration andwashing extensively with methanol and CH₂Cl₂. The filtrate and washingswere combined and concentrated. The residue was purified by thin layerchromatography (12% MeOH/CH₂Cl₂) to give the title compound as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2H), 1.70-1.90 (m, 2H),2.50-2.80 (m, 5H), 3.45-3.60 (m, 2H), 3.80-4.00 (m, 3H), 4.95 (brs, 1H), 5.24 (brs, 1 H), 6.81 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H),6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H), 7.41 (d, J=9.0 Hz, 2 H), 7.75(d, J=9.0 Hz, 2 H), 8.53 (d, J=2.0 Hz, 1 H), 8.62 (d, J=2.0 Hz, 1 H); MS(ES) m/z: 677.0 (MH⁺); HRMS Calcd. for C₃₂H₃₃F₃N₄O₅SCl (MH⁺): 677.1812.Found: 677.1816. Anal. Calcd. for C₃₂H₃₂F₃N₄O₅SCl: C, 56.70; H, 4.76; N,8.27. Found: C, 56.58; H, 4.90; N, 8.03.

EXAMPLE 347N-{[5-({4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)-2-thienyl]methyl}benzamide

[0705] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), (2-benzoylaminomethyl)thiophene-5-sulphonyl chloride, and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 346; MS(ES) m/z: 677.4 (MH⁺).

EXAMPLE 348N-[(5-{4-(4-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide

[0706] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), (2-benzoylaminomethyl)thiophene-5-sulphonyl chloride, and(2S)-1-amino-3-phenoxy-propan-2-ol according to the procedure of Example346; MS (ES) m/z: 621.4 (MH⁺).

EXAMPLE 349N-[(5-{[4-(4-{[2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)-anilino]sulfonyl}-2-thienyl)methyl]benzamide

[0707] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), (2-benzoylaminomethyl)thiophene-5-sulphonyl chloride, andDL-norphenylephrine according to the procedure of Example 346; MS (ES)m/z: 607.4 (MH⁺).

EXAMPLE 3504-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-benzenesulfonamide

[0708] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonylchloride, and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 346; MS(ES) m/z: 733.3 (MH⁺).

EXAMPLE 3514-{3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide

[0709] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonylchloride, and DL-norphenylephrine according to the procedure of Example346; MS (ES) m/z: 663.2 (MH⁺).

EXAMPLE 3523,5-Dichloro-4-(2-chloro-4-nitrophenoxy)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-benzenesulfonamide

[0710] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), 4-(2-chloro-4-nitrophenoxy)-3,5-dichlorobenzenesulfonylchloride, and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S.Pat. No. 5,786,356/1998) according to the procedure of Example 346; MS(ES) m/z: 777.2, 779.2 (MH⁺).

EXAMPLE 3533,5-Dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide

[0711] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), 4-(2-chloro-4-nitrophenoxy)-3,5-dichlorobenzenesulfonylchloride, and (2S)-1-amino-3-phenoxy-propan-2-ol according to theprocedure of Example 346; MS (ES) m/z: 723.2, 725.2 (MH⁺).

EXAMPLE 3543,5-Dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)-ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide

[0712] The title compound was prepared from1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained inExample 224), 4-(2-chloro-4-nitrophenoxy)-3,5-dichlorobenzenesulfonylchloride, and DL-norphenylephrine according to the procedure of Example346; MS (ES) m/z: 709.1, 711.1 (MH⁺).

EXAMPLE 355N-[4-(4-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino)-1-piperidinyl)phenyl]-2-thiophenesulfonamide

[0713] The title compound was prepared according to the procedure ofExample 346 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.81-0.83(m, 1H), 1.23-1.36 (m, 3H), 1.84-1.88 (m, 2H), 2.61-2.73 (m, 4H), 3.53(d, J=12.03 Hz, 3H), 3.95-4.04 (m, 2H), 5.02 (brs. 1H), 6.80 (d, J=9.09Hz, 1H), 6.89-6.94 (m, 6H), 7.08-7.11 (m, 2H), 7.24-7.30 (m, 1H), 7.40(dd, J=1.29 Hz, 5.01 Hz, 1H), 7.86 (dd, J=1.29 Hz, 3.69 Hz, 1H); MS (ES)m/z: 488.0 (MH⁺); HRMS found for C₂₄H₂₉N₃O₄S₂: 488.1691.

EXAMPLE 3564-Butoxy-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)-phenyl]benzenesulfonamide:

[0714] The title compound was prepared according to the procedure ofExample 346 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.91 (t,J=7.32 Hz, 3H), 1.24-1.35 (m, 2H), 1.39-1.50 (m, 2H), 1.63-1.72 (m, 2H),1.82-1.91 (m, 2H), 2.57-2.65 (m, 4H), 2.69-2.72 (m, 2H), 3.13-3.19 (m,1H), 3.46-3.52 (m, 2H), 3.83-3.90 (m, 2H), 3.92-4.01 (m, 2H), 4.98 (brs,1H), 5.21-5.25 (m, 1H), 6.76 (d, J=9.09 Hz, 2 H), 6.85-6.95 (m, 2 H),7.01 (d, J=8.94 Hz, 2H), 7.24-7.31 (m, 4 H), 7.57 (d, J=8.88 Hz, 2H),8.04 (s, 1 H); MS (ES) m/z: 554.5 (MH⁺); HRMS found for C₃₀H₃₉N₃O₅S:554.2685.

EXAMPLE 357N-[4-(4-{[(2S)-2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]-2-thiophenesulfonamide

[0715] The title compound was prepared according to the procedure ofExample 346 as a light green solid; 1H NMR (300 MHz, DMSO-d₆) δ0.81-0.90(m, 1H), 1.24-1.35 (m, 2H), 1.87-1.91 (m, 2H), 2.59-2.73 (m, 4H),3.40-3.47 (m, 2H), 3.53-3.57 (m, 2H), 4.53 (brs, 2H), 5.31 (brs, 1H),6.62 (d, J=7.68 Hz, 1 H), 6.75 (d, J=8.64, 1H), 6.82 (d, J=9.09, 3H),6.92 (d, J=8.97 Hz, 1H), 7.07-7.12 (m, 2H), 7.41 (dd, J=1.26 Hz, 3.75Hz, 1H), 7.86 (dd, J=1.14 Hz, 4.92 Hz, 1H), 9.29 (s, 1 H); MS (ES) m/z:474.0 (MH⁺); HRMS found for C₂₃H₂₇N₃O₄S₂: 474.1522.

EXAMPLE 3584-Butoxy-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide

[0716] The title compound was prepared according to the procedure ofExample 346 as a brownish solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.89-0.95(m, 3H), 1.35-1.49 (m, 2H), 1.64-1.73 (m, 2H), 1.90-2.02.(m, 1H),2.58-2.62 (m, 1 H), 2.90-3.05 (m, 1H), 3.13-3.16 (m, 1H), 3.62-3.66(brd, 1H), 3.89-4.06 (m, 2H), 5.06-5.08 (d, J=4.86 Hz, 1H), 5.48 (brs,1H), 6.56-6.70 (m, 3H), 6.79-6.91 (m, 8 H), 7.01-7.04 (d, J=8.91 Hz,2H), 7.46-7.54 (m, 2H), 7.57-7.60 dd, J=1.83 Hz, 8.88 Hz, 2H) 8.04 (s,1H), 8.16 (s, 1H), 9.66 (brs, 1H), 10.55-10.65 (m, 2H), 10.7 (s, 1H); MS(ES) m/z: 610.4 (MH⁺); HRMS found for C₃₁H₃₉N₅O₆S: 610.2707.

EXAMPLE 359N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide

[0717] The title compound was prepared according to the procedure ofExample 346 as a gray solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.49-1.55 (m,2H), 1.99-2.17 (m, 2H), 2.58-2.65 (m, 2H), 2.85-2.98 (m, 2H), 3.07-3.09(m, 2H), 3.59-3.63 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.01 (s, 3H),5.35 (brs, 1H), 6.57-6.64 (m, 2H), 6.79-6.92 (m, 5H), 7.018-7.046 (d,J=8.4 Hz, 1H), 7.18-7.25 (m, 2H), 8.18 (s, 1H), 9.62 (brs, 1H), 10.61(s, 1H), 10.72 (s, 1H); MS (ES) m/z: 598.1 (MH⁺); HRMS found forC₂₉H₃₅N₅O₇S: 598.2348.

EXAMPLE 360N-[4-(4-{[(2S)-2-Hydroxy-3-phenoxvpropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0718] The title compound was prepared according to the procedure ofExample 346 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ0.85-0.90(m, 1H), 1.24-1.51 (m, 2H), 1.82-1.90 (m, 2H), 2.58-2.70 (m, 4H),3.48-3.52 (m, 2H), 3.71 (s, 3H), 3.78 (s, 3H), 3.84-3.92 (m, 2H), 4.99(brs, 1H), 5.23-5.25 (m, 1H), 6.76 (s, 1H), 6.79(s, 1H), 6.86-6.94 (m,2H), 7.01 (s, 1H), 7.04 (s, 1H), 7.16 (d, J=2.13 Hz, 2H), 7.20-7.21 (d,J=2.1 Hz, 1H), 7.23-7.24 (m, 1H), 7.26-7.29 (m, 2H), 7.66-7.72 (m, 1H),8.08 (s, 1H), 9.56 (brs, 1H); MS (ES) m/z: 542.1 (MH⁺); HRMS found forC₂₈H₃₅N₃O₆S: 542.2330.

EXAMPLE 361N-[4-(4-{[2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0719] The title compound was prepared according to the procedure ofExample 346 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.35-1.40(m, 2H), 1.64 (m, 1H), 1.85-1.95 (m, 2H), 2.72-2.73 (m, 2H), 2.80 (m,2H), 3.52-3.57 (m, 2H), 3.71 (s, 3H), 3.78 (s, 3H), 4.58 (m, 1H), 5.55(brs, 1H), 6.62-6.65 (m, 1H), 6.74-6.81 (m, 3H), 6.89 (d, J=9.0 Hz, 1H),7.01 (s, 1H), 7.04 (s, 1H), 7.08-7.14 (m, 1H), 7.17 (d, J=8.01 Hz, 1H),7.21 (d, J=2.13 Hz, 1H), 7.24 (d, J=2.07 Hz, 1H), 9.34 (s, 1H), 9.55(brs, 1H); MS (ES) m/z: 528.1 (MH⁺); HRMS found for C₂₇H₃₃N₃O₆S:528.2160.

EXAMPLE 362N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide

[0720] The title compound was prepared according to the procedure ofExample 346 as a greenish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.38 (m,2H), 1.91 (m, 2H), 2.64 (t, 2H), 2.54 (t, 2H), 2.75 (m, 2H), 2.85 (m,2H), 3.15 (d, 1H), 3.55 (m, 2H), 3.93-3.96 (m, 2H), 5.05 (brs, 1H), 6.57(d, J=5.7 Hz, 1H), 6.61 (d, J=6.3 Hz, 1H), 6.81-6.87 (m, 2H), 6.92 (d,J=6.9 Hz 1H), 7.10 (t, J=3.6 Hz, 1 H), 7.41(d, J=2.1 Hz, 1H), 7.86 (d,J=3.6 Hz, 1H), 10.6 (s, 1H), 10.7 (s, 1H); MS (ES) m/z: 544.0 (MH⁺);HRMS found for C₂₅H₂₉N₅O₅S₂: 544.1709.

EXAMPLE 363 Ethyl 3-oxo-3-[4-(4-oxo-1-piperidinyl)anilino]propanoate

[0721] To a stirred solution, under N₂ atmosphere, of1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained inExample 224)(10.0 g, 38 mmol), and triethylamine (15.35 g, 150 mmol) inmethylene chloride (100 mL) was added ethyl 3-chloro-3-oxopropionate(6.32 g, 42 mmol). The reaction was stirred for 18 hours. The reactionmixture was concentrated down in vaco and purified by flash silica gelchromatography eluting with 1:1 ethyl acetate/hexanes to give an orangesolid (0.86 g, 7%); ¹H NMR (300 MHz, CDCl₃) δ1.32 (t, J=7.2 Hz, 3 H),2.55 (t, J=6 Hz, 4 H), 3.46 (s, 2 H), 3.56 (t, J=6 Hz, 4 H), 4.22 (q,J=7.2 Hz, 2 H), 6.93(d, J=9.0 Hz, 2 H), 7.47(d, J=9.0 Hz, 2 H), 9.09 (s,1 H); MS (ES) m/z: 305.3(MH⁺, 100%).

EXAMPLE 364 Ethyl3-[butyl-4-(4-oxo-1-piperidinyl)anilino]-3-oxopropanoate

[0722] A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane(13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10%palladium on carbon (2.5 g) as catalyst. The reaction mixture wasfiltered through celite pad and the filtrate was concentrated down togive a white solid (11.46 g, 100%). This material was taken onto nextstep immediately. To a stirred mixture, under N₂ atmosphere, of theaniline (11.46 g, 49 mmol), butryaldehyde (4.43 mL, 49 mmol) intetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.62g, 68.6 mmol), and glacial acetic acid (2.82 mL, 49 mmol). The reactionwas stirred for two hours. The reaction was quenched with 1 N NaOH (50mL), diluted with water, extracted with ether 3 times and dried oversodium sulfate. The product was purified by flash silica gelchromatography eluting with 1:1 ethyl acetate/hexanes to give an oil(5.80g, 41%). This material was immediately taken onto next step. Asolution of the N-butyl aniline (5.80 g, 19.9 mmol) in a 1:1 mixture ofperchloric acid and hydrochloric acid (100 mL) was stirred at roomtemperature for three days. The reaction mixture was poured onto ice andmade basic with concentracted ammonium hydroxide, extracted with etherfour times, dried over sodium sulfate and concentrated to give a yellowoil. The yellowish oil was purified by flash silica gel chromatographyeluting with 1:1 ethyl acetate/hexanes to give1-[4-(butylamino)phenyl]-4-piperidinone as an oil (3.84 g, 82%). To astirred mixture of 1-[4-(butylamino)phenyl]-4-piperidinone (2.46 g, 10mmol), triethylamine (1.81 mL, 13 mmol), and 4-(dimethylamino)pyridine(DMAP) (catalytic amount) was added ethyl 3-chloro-3-oxopropionate (2.18g, 13 mmol) dropwise. The reaction was stirred for 18 hours. Thereaction mixture was filtered, concentrated in vacuo, taken up inmethylene chloride, and washed with saturated sodium bicarbonate twotimes and dried over sodium sulfate. The product was purified by flashsilica gel chromatography eluting with 1:1 ethyl acetate/hexanes to givea yellow oil (3.84 g, 68%); MS (ES) m/z: 361.3(MH⁺, 100%).

EXAMPLE 365 3-[Cyclohexyl-4-(4-oxo-1-piperidinyl)anilino]-3-oxopropanoicacid

[0723] A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane(13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10%palladium on carbon (2.5 g) as catalyst. The reaction mixture wasfiltered through celite pad and the filtrate was concentrated down togive a white solid (11.46 g, 100%). This material was taken onto nextstep immediately. To a stirred mixture, under N₂ atmosphere, of theaniline (10.99 g, 47 mmol), cyclohexanone (4.90 mL, 47 mmol) intetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.05g, 66 mmol), and glacial acetic acid (2.71 mL, 47 mmol). The reactionwas stirred for one hour. The reaction was quenched with 1 N NaOH (50mL), diluted with water, extracted with ether 3 times and dried oversodium sulfate. The product was isolated as an oil (14.85 g, 100%). Thismaterial was immediately taken onto next step without furtherpurification. A solution of N-cyclohexyl aniline (14.85 g, 47 mmol) inhydrochloric acid (100 mL) was stirred at room temperature for 18 hours.The reaction mixture was poured onto ice and made basic withconcentrated ammonium hydroxide, extracted with ether four times, driedover sodium sulfate and concentrated to give a yellow oil. The productwas used without further purification (12.78 g, 100%). To a stirredmixture of the ketone (12.78 g, 47 mmol), triethylamine (8.49 mL, 61mmol), and DMAP (catalytic amount) was added ethyl3-chloro-3-oxopropionate (9.19 g, 61 mmol) dropwise. The reaction wasstirred for 18 hours. The reaction mixture was filtered and concentratedin vacuo to give an oil (3.48 g, 19%).

[0724] To a stirred solution of 1N sodium hydroxide (6 mL) was added theoil (3.11 g, 8.1 mmol). The reaction-was stirred for 18 hours. Thereaction mixture was brought to a pH of 6 with acetic acid, extractedwith ethyl acetate, and dried over sodium sulfate. The product waspurified by flash chromatography on reverse phase silica gel eluting70:30 methanol/water to give a yellow solid (1.36 g, 47%). MS (ES) m/z:359.2 (MH⁺, 100%); HRMS Calcd. for C₂₀H₂₆N₂O₄(2M−H)⁻: 715.3711. Found:715.3707.

EXAMPLE 366 {3-[4-(4-Oxo-piperidin-1-yl)-phenyl1-ureido}-acetic acidethyl ester

[0725] Isocyanatoacetate (1.76 g,, 13.6 mmol) in 10 mL of methylenechloride was added dropwise to a stirred solution of1-(4-amino-phenyl)-piperidin-4-one (2,60 g, 13.6 mmol)(which wasobtained in Example 224) in 100 mL of methylene chloride at roomtemperature. After stirring for 3 hours the solvent was removed and theresidue was washed with hexanes to give the title compound as a palebrown solid (2.0 g, 46%); ¹H NMR (300 MHz, DMSO-d₆) δ1.20(t, J=7.1 Hz, 3H), 2.41 (t, J=6.0 Hz, 4 H), 3.48 (t, J=6.0 Hz, 4 H), 3.83 (d, J=5.8 Hz,2 H); 4.10 (q, J=7.1 Hz, 2 H), 6.31 (t, J=5.8 Hz, 2 H), 6.94(d, J=9.0Hz, 2 H), 7.26 (d, J=9.0 Hz, 1 H), 8.52(s, 1 H); MS (ES) m/z: 320.5(MH⁺); HRMS Calcd. for C₂₀H₂₈N₂O₄(M⁺): 319.1532. Found: 319.1540.

EXAMPLE 367 Ethyl({[butyl-4-(4-oxo-1-piperidinyl)anilino]carbonyl}amino)acetate

[0726] The title compound was prepared from ethyl isocyanatoacetate and1-[4-(butylamino)phenyl]-4-piperidinone (which was obtained in Example364) according to the procedure of Example 366 as a pale brown solid; MS(ES) m/z: 376.5 (MH⁺).

EXAMPLE 368 N-[4-(4-Oxo-piperidin-1-yl)-phenyl]-butyramide

[0727] Butyryl chloride (0.31 mL, 2.94 mmol) was added to a solution ofN-[4-(4-oxo-piperidin-1-yl)-phenyl]amine (which was obtained in Example224) (0.70 g, 2.77 mmol) and triethylamine (1.9 mL, 13.9 mmol) inanhydrous methylene chloride (10 mL). The reaction was stirredovernight. The reaction was quenched with water (50 mL) and washed withmethylene chloride (3×20 mL). The organic extracts were combined, dried(sodium sulfate) and concentrated. The desired product was isolatedusing silica gel flash chromatography to give the title compound as ayellow solid (0.41 g); ¹H NMR (300 MHz, CDCl₃) δ1.01 (t, 3H, J=7.38 Hz),1.72 (m, 2H), 2.29(t, 2H, J=7.62 Hz), 2.55(t, 4H, J=6.03 Hz), 3.55(t,4H, J=5.97 Hz), 6.95(d, 2H, J=7.91), 7.42(d, 2H, J=8.97 Hz). MS (ES)m/z: 260.9(MH⁺); HRMS found for C₁₅H₂₀N₂O₂: 260.1511. Anal. Calcd. forC, 69.20; H, 7.74, N, 10.76. Found: C, 69.03; H, 7.94; N, 10.59.

EXAMPLE 369 3,4-Dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzamide

[0728] The title compound was prepared according to the procedure ofExample 368 as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ2.42(t, 4H,J=5.94 Hz), 3.56(t, 4H, J=6.03 Hz), 3.81(s, 3H), 3.84(s, 3H), 7.05(m,3H), 7.52(d, 1H, 2.10 Hz), 7.62(m, 3H), 9.97(s, 1H). MS (ES) m/z:355.0(MH⁺); HRMS found for C₂₀H₂₂N₂O₄: 354.1577.

EXAMPLE 370 2-Chloro-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-acetamide

[0729] The title compound was prepared according to the procedure ofExample 368 as a dark blue solid; ¹H NMR (300 MHz, CDCl₃) δ2.55(t, 4H,J=5.88 Hz), 3.58(t, 4H, J=5.91 Hz), 4.19(s, 2H), 6.97(d, 2H, J=8.67 Hz),7.47(d, 2H, 8.94 Hz), 8.17(brs, 1H). MS (ES) m/z: 266.8(MH⁺); HRMS foundfor C₁₃H₁₅N₂O₂: 266.0805.

EXAMPLE 371 Ethyl3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)-amino]-1-piperidinyl}anilino)-3-oxopropanoate

[0730] To a stirred solution ofN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanessulfonamide(which was obtained in Example 10)(0.3 g, 1.2 mmol) and ethyl3-oxo-3-[4-(4-oxo-1-piperidinyl)anilino]propanoate (which was obtainedin. Example 363) (0.39 g, 1.28 mmol) in dimethylformamide (8 mL) undernitrogen atmosphere was added sodium triacetoxyborohydride (0.34 g, 1.59mmol) and glacial acetic acid (0.08 g, 1.3 mmol). The mixture wasstirred at room temperature for 3 days. The reaction was quenched withsaturated sodium bicarbonate, extracted with ethyl acetate three times,dried over sodium sulfate, and concentrated. The product was purified byflash silica gel chromotagraphy eluting with 20% methanol in methylenechloride to give the title compound as a yellow solid (0.23 g, 36%); ¹HNMR (300 MHz, DMSO-d₆) δ1.19(t, J=7.0 Hz, 3 H), 1.25-1.45 (m, 2 H),1.75-1.95 (m, 2 H, 2.50-2.70 (m, 5 H), 2.92 (s, 3 H), 3.33(s, 2 H),3.45-3.60 (m, 2 H), 4.09(q, J=7.0 Hz, 2 H). 4.48(dd, J=8.1, 4.2 Hz, 1H), 6.80(d, J=8.3 Hz, 1 H), 6.90(d, J=9.0 Hz, 2 H), 7.00(dd, J=8.3, 2.0Hz, 1 H), 7.18 (d, J=2.0 Hz, 1 H), 7.39(d, J=9.0 Hz, 2 H), 9.92(s, 1 H);MS (ES) m/z: 535.3 (MH⁺); HRMS Calcd. for C₂₅H₃₅N₄O₇S (MH⁺): 535.2221.Found: 535.2208.

EXAMPLE 3723-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid

[0731] To a stirred solution of ethyl3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate(which was obtained in Example 371)(0.23 g, 0.43 mmol) in distilledwater (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL).The reaction was stirred at room temperature for 1 hr. The reactionmixture was made acidic (pH 6) with glacial acetic acid, concentrated,triturated with water, ether, ethyl acetate to give the title compoundas a light yellow solid (0.13 g, 59%); ¹H NMR (300 MHz, DMSO-d₆)δ1.30-1.45(m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.80 (m, 5 H), 2.90 (s, 2H), 2.91 (s, 3 H), 3.45-3.60 (m, 2 H), 4.48-4.53(m, 1 H), 6.80-6.90(m,3H), 7.00(d, J=8.3 Hz, 1 H), 7.18 (d, J=1.6 Hz, 1 H), 7.38(d, J=9.0 Hz,2 H), 11.50-11.60(m, 1 H); MS (ES) m/z: 505.3 (M−H)⁻; HRMS Calcd. forC₂₃H₃₁N₄O₇S (MH⁺): 507.1908. Found: 507.1895.

EXAMPLE 373 Ethyl3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate

[0732] To a stirred solution, under nitrogen atmosphere, ofN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanessulfonamide(which was obtained in Example 10) (0.85 g, 3.5 mmol) and ethyl3-[butyl-4-(4-oxo-1-piperidinyl)anilino]-3-oxopropanoate (which wasobtained in Example 364) (1.47 g, 3.7 mmol)in methylene chloride (15mL), dimethylformamide (5 mL) was added trimethyl orthoformate (1.53 mL,14.0 mmol). The mixture was stirred for 2 hours before sodiumtriacetoxyborohydride (1.04 g, 4.9 mmol) and glacial acetic acid (0.2mL, 3.5 mmol) was added. The reaction was stirred for 18 hours at roomtemperature. The reaction mixture was poured onto 1:1 water/saturatedsodium bicarbonate, extracted with 10% methanol in methylene chloride,dried over sodium sulfate, and concentrated. The product was purified byflash chromatography on normal phase silica gel eluting with 10%methanol in methylene chloride, then with 15% methanol in methylenechloride, and then flash chromatograph on reverse phase silica geleluting with methanol to give the titled compound as a tan solid (0.6 g,29%); ¹H NMR (300 MHz, DMSO-d₆) δ0.81(t, J=7.0 Hz, 3 H), 1.11(t, J=7.0Hz, 3 H), 1.20-1.50(m, 6 H), 1.80-2.00 (m, 2 H), 2.65-2.90 (m, 5 H),2.93 (s, 3 H), 3.09(s, 2 H), 3.56(t, J=6.8 Hz, 2 H), 3.65-3.80 (m, 2 H),3.97(q, J=7.0 Hz, 2 H), 4.55-4.65(m, 1 H), 6.85(d,J=8.3 Hz, 1 H),6.96(d, J=9.0 Hz, 2 H), 7.00-7.10(m, 3 H), 7.20 (d, J=2.0 Hz, 1 H); MS(ES) m/z: 591.2(MH⁺); HRMS Calcd. for C₂₉H₄₂N₄O₇S(M⁺): 590.2774.Found:590.2847.

EXAMPLE 3743-(Butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid

[0733] To a stirred solution of ethyl3-(butyl-4-(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-l)ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate(which was obtained in Example 373)(0.23 g, 0.39 mmol) in distilledwater (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL).The reaction was stirred at room temperature for 1 hour. The mixture wasacidified (pH 6) with glacial acetic acid, concentrated, triturated withwater, ethyl acetate, ether, and dried under vacuum to give the titledcompound as a tan solid (0.04 g, 19%); ¹H NMR (300 MHz, DMSO-d₆)δ1.20-1.50(m, 6 H), 1.70-1.95 (m, 2 H), 2.60-2.80 (m, 5 H), 2.83 (s, 2H), 2.91(s, 3 H), 3.45-3.70 (m, 4 H), 4.55-4.65(m, 1 H), 6.81 (d, J=8.0Hz, 1 H), 6.90(d, J=8.7 Hz, 2 H), 7.09 (d, J=8.7 Hz, 2 H), 7.07(s, 1 H);MS (ES) m/z: 563.2(MH⁺); HRMS Calcd. for C₂₇H₃₉N₄O₇S(MH⁺): 563.2461.Found: 563.2526.

EXAMPLE 375 Ethyl3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate

[0734] A solution of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane(13.01 g, 49 mmol) was hydrogenated under 45 psi for one hour using 10%palladium on carbon (2.5 g) as catalyst. The reaction mixture wasfiltered through celite pad and the filtrate was concentrated down togive a white solid (11.46 g, 100%). This material was taken onto nextstep immediately. To a stirred mixture, under N₂ atmosphere, of theaniline (10.99 g, 47 mmol), cyclohexanone (4.90 mL, 47 mmol) intetrahydrofuran (250 mL) was added sodium triacetoxyborohydride (14.05g, 66 mmol), and glacial acetic acid (2.71 mL, 47 mmol). The reactionwas stirred for one hour. The reaction was quenched with 1 N NaOH (50mL), diluted with water, extracted with ether 3 times and dried oversodium sulfate. The product was isolated as an oil (14.85 g, 100%).:This material was immediately taken onto next step without furtherpurification. A solution of the N-cyclohexyl aniline (14.85 g, 47 mmol)in hydrochloric acid (100 mL) was stirred at room temperature for 18hours. The reaction mixture was poured onto ice and made basic withconcentrated ammonium hydroxide, extracted with ether four times, driedover sodium sulfate and concentrated to give a yellow oil. The productwas used without further purification (12.78 g, 100%). To a stirredmixture of the ketone (12.78 g, 47 mmol), triethylamine (8.49 mL, 61mmol), and DMAP (catalytic amount) was added ethyl3-chloro-3-oxopropionate (9.19 g, 61 mmol) dropwise. The reaction wasstirred for 18 hours. The reaction mixture was filtered and concentratedin vacuo to give an oil (3.48 g, 19%).

[0735] To a stirred solution, under nitrogen atmosphere, ofN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanessulfonamide(which was obtained in Example 10)(0.20 g, 0.81 mmol). and the oil (0.37g, 0.81 mmol) in methylene chloride (10 mL), dimethylformamide (2 mL)was added trimethyl orthoformate (0.35 mL, 3.2 mmol). The mixture wasstirred for 18 hours before sodium triacetoxyborohydride (0.24 g, 1.1mmol) and glacial acetic acid (0.047 mL, 0.81 mmol) were added. Themixture was stirred an additional 24 hours. The mixture was poured onto1:1 water/saturated sodium bicarbonate, extracted with 10% methanol inmethylene chloride, dried over sodium sulfate, and concentrated. Theproduct was purified by flash chromatography. on normal phase silica geleluting with 15% methanol in methylene chloride, and then flashchromatographed on reverse phase silica gel eluting with methanol togive the title compound as a tan solid (0.12 g, 24%); ¹H NMR (300 MHz,DMSO-d₆) δ0.60-1.00(m, 4 H), 1.11(t, J=7.0 Hz, 3 H), 1.15-1.80(m, 8 H),1.80-2.00 (m, 2 H), 2.65-2.80 (m, 5 H), 2.93 (s, 3 H), 2.97(s, 2 H),3.65-3.80 (m, 2 H), 3.97(q, J=7.0 Hz, 2 H), 4.25-4.40(m, 1H),4.50-4.60(m, 1 H), 6.85(d, J=8.3 Hz, 1 H), 6.90-7.00(m, 4 H), 7.03(dd,J=8.3, 2.0 Hz, 1 H), 7.20 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 617.2(MH⁺);HRMS Calcd. for C₃₁H₄₄N₄O₇S(M⁺): 616.2932. Found: 617.3001.

EXAMPLE 3763-(Cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid

[0736] A mixture ofN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanessulfonamide(which was obtained in Example 10) (0.28 g, 1.1 mmol),3-[cyclohexyl-4-(4-oxo-1-piperidinyl)anilino]-3-oxopropanoic acid (whichwas obtained in Example 365) (0.41 g, 1.1 mmol), glacial acetic acid (1mL), and 10% palladium on carbon in anhydrous methanol (75 mL) washydrogenated under 20 psi for 18 hours. The mixture was filtered throughcelite. The filtrate was concentrated. The product was triturated withhot ether,, and then with methanol to give the title compound as a tansolid (0.03 g, 4.6%); ¹H NMR (300 MHz, DMSO-d₆) δ0.80-1.05(m, 4 H),1.15-1.60(m, 4 H), 1.60-1.75(m, 4 H), 1.90-2.05 (m, 2 H), 2.65-2.90 (m,5H), 2.83 (s, 2 H), 2.93(s, 3 H), 3.65-3.80 (m, 2 H), 4.30-4.45(m, 1 H),4.60-4.70(m, 1 H), 6.85(d, J=8.3 Hz, 1 H), 6.95(d, J=9.1 Hz, 2 H),7.02(d, J=9.1 Hz, 2 H), 7.05 (d, J=8.3 Hz, 1 H), 7.22(s, 1 H); MS (ES)m/z: 587.3(M−H)⁻; HRMS Calcd. for C₂₉H₄₁N₄O₇S(M⁺+H): 589.2690. Found:589.2690.

EXAMPLE 377 Ethyl{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate

[0737] The title compound was prepared from{3-[4-(4-oxo-piperidin-1-yl)-phenyl]-ureido}-acetic acid ethyl ester(which was obtained in Example 366) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, J=7.1 Hz, 3H), 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.70 (m, 5 H), 2.92 (s,3 H, 3.40-3.50 (m, 2 H), 3.83 (d, J=5.9 Hz, 2 H), 4.10 (q, J=7.1 Hz, 2H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 6.28 (t, J=5.9 Hz, 1 H), 6.75-6.85(m, 3 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.15-7.25 (m, 3 H), 8.45 (s, 1H); MS (ES) m/z: 550.5 (MH⁺); HRMS Calcd. for C₂₅H₃₆N₅O₇S (MH⁺):550.2330. Found: 550.2319.

EXAMPLE 378{[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}aceticacid

[0738] The title compound was prepared from ethyl{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl)ethyl)amino]-1-piperidinyl}anilino)carbonyl]-amino)acetate(which was obtained in Example 377) by NaOH hydrolysis as a white solid;1H NMR (300 MHz, DMSO-d₆) δ1.35-1.55 (m, 2 H), 1.80-2.00 (m, 2 H),2.50-2.90 (m, 5 H), 2.92 (s, 3 H), 3.30-3.50 (m, 2 H), 3.59 (d, J'5.9Hz, 2 H), 4.60 (dd, J=8.8, 3.5 Hz, 1 H), 6.14 (t, J=5.0 Hz, 1 H), 6.80(d, J=9.1 Hz, 2 H), 6.84 (d, J=8.3 Hz, 1 H), 7.03 (dd, J=8.3, 2.0 Hz, 1H), 7.15-7.25 (m, 3 H), 8.54 (s, 1 H); MS (ES) m/z: 520.3 (M−H)⁻; HRMSCalcd. for C₂₃H₃₂N₅O₇S (MH⁺): 522.2017. Found: 522.2000.

EXAMPLE 379 Ethyl{[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl-ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate

[0739] The title compound was prepared from ethyl({[butyl-4-(4-oxo-1-piperidinyl)anilino]carbonyl}amino)acetate (whichwas obtained in Example 367) andN-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Example 10) according to the procedure of Example278 as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ0.83 (t, J=7.1 Hz, 3H), 1.17 (t, J=7.1 Hz, 3 H), 1.15-1.40 (m, 6 H), 1.80-1.95 (m, 2 H),2.50-2.80 (m, 5 H), 2.90 (s, 3 H), 3.49 (t, J=6.9 Hz, 2 H), 3.55-3.60(m, 2 H), 3.65 (d, J=5.9 Hz, 2 H), 4.04 (q, J=7.1 Hz, 2 H), 4.48 (dd,J=7.9, 4.4 Hz, 1 H), 5.60 (t, J=5.9 Hz, 1 H), 6.80 (d, J=8.2 Hz, 1 H),6.90-7.10 (m, 5 H), 7.17 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 606.3 (MH⁺);HRMS Calcd. for C₂₉H₄₄N₅O₇S (MH⁺): 606.2956. Found: 606.2955.

EXAMPLE 380{[(Butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino}phenyl}ethyl)-amino-1-piperidinyl}anilino)carbonyl]amino}aceticacid

[0740] The title compound was prepared from ethyl{[(butyl-4-(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate(which was obtained in Example 379) by NaOH hydrolysis as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ0.83 (t, J=7.1 Hz, 3 H), 1.15-1.60 (m, 6 H),1.85-2.00 (m, 2 H), 2.65-2.95 (m, 5 H), 2.92 (s, 3 H), 3.42 (d, J=4.0Hz, 2 H), 3.45-3.55 (m, 2 H), 3.65-3.80 (m, 2 H), 4.65-4.75 (m, 1 H),5.16 (t, J=4.0 Hz, 1 H), 6.83 (d, J=8.3 Hz, 1 H), 6.95-7.15 (m, 5 H),7.20 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 576.3 (M−H)⁻; HRMS Calcd. forC₂₇H₃₈N₅O₇S (M−H)⁻: 576.2497. Found: 576.2502.

EXAMPLE 381N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1piperidinyl]phenyl}-3,4-dimethoxybenzamide

[0741] Sodium triacetoxyborohydride (0.044 g, 2.1 mmol) was added to asolution of4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S.Pat. No. 5,786,356) (0.23 g, 1.05 mmol),3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzamide (which wasobtained in Example 369) (0.41 g, 1.16 mmol), and acetic acid(0.07 mL,1.16 mmol) in anhydrous dimethylforamide(8 mL). The reaction was stirredfor 2 hours. The reaction was quenched with 50% water/saturated aqueousNaHCO₃(20 mL). The solids were captured on a filter and washed withethyl acetate, diethyl ether, and hexanes to afford 0.319 of the desiredproduct as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.32 (m, 2H), 1.89(m, 2H), 2.54 (m, 1H), 2.65 (m, 2H), 2.84(m, 2H), 3.56 (m, 2H), 3.83(s,3H), 3.84 (s, 3H), 3.95 (m, 2H), 4.02 (s, 1H), 5.06(brs, 1H), 6.52 (d,1H, J 7.1), 6.51(d, 1H, J=8.1 Hz), 6.88 (m, 2H), 7.08 (d, 1H, J=8.7 Hz),7.58 (m, 5H), 8.87 (s, 1 H), 10.59 (brs, 1 H),10.72 (brs, 1 H); MS (ES)m/z: 561.2 (MH⁺).

EXAMPLE 3822-Chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide

[0742] The title compound was prepared according to the procedure ofExample 381 as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.31(m, 2H), 1.88(m, 2H), 2.56 (m, 1H), 2.67 (m, 2H), 2.79(m, 2H), 3.54 (m, 2H), 3.95(s,2H), 4.06 (m, 1H), 4.19 (s, 2H), 4.91(brs, 1H), 6.56 (d, 1H, J=7.8),6.64(d, 1H, J=8.1 Hz), 6.88 (m, 3H), 7.39 (d, 2H, J=9.0 Hz), 10.06 (s,1H); MS (ES) m/z: 474.0 (MH⁺); HRMS found for C₂₃H₂₈Cl N₅O₄: 474.1934.

EXAMPLE 383N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-2-(4-morpholinyl)acetamide

[0743] The title compound was prepared according to the procedure ofExample 381 as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.35(m, 2H),1.88 (m, 2H), 2.61 (m, 2H), 2.69 (m, 2H), 2.79(m, 2H), 3.07(s, 2H),3.48(m, 4H), 3.64(t, 4H, J=4.23), 3.96(m, 3H), 5.11(brs, 1H), 6.58 (d,1H, J=7.8), 6.64(d, 1H, J=8.4 Hz), 6.85(m, 3H), 7.46(d, 2H, J=8.7 Hz),9.47(s, 1H); MS (ES)m/z: 525.1 (MH⁺); HRMS found for C₂₇H₃₆N₆O₅:524.2719.

EXAMPLE 3842-(Dimethylamino)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide

[0744] The title compound was prepared according to the procedure ofExample 381 as a dark brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.36(m,2H), 1.89 (m, 2H), 2.27(s, 6H), 2.61 (m, 2H), 2.79(m, 2H), 3.00(s, 2H),3.36(m, 1H), 3.54(m, 2H), 3.96(m, 3H), 4.98(brs, 1H), 6.58 (d, 1H,J=7.8), 6.64(d, 1H, J=8.4 Hz), 6.85(m, 3H), 7.46(d, 2H, J=9.0 Hz),10.59(brs, 1H), 10.71(brs, 1H); MS (ES) m/z: 483.1 (MH⁺); HRMS found forC₂₅H₃₄N₆O₄: 483.2769.

EXAMPLE 385N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-dimethoxybenzamide

[0745] The title compound was prepared according to the procedure ofExample 381 as a dark brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.35(m,2H), 1.89 (m, 2H), 2.70 (m, 3H), 2.85(m, 1H), 3.60(m, 3H), 3.82(s, 3H),3.83(s, 3H), 4.50(m, 1H), 6.93 (m, 2H), 7.03(m, 2H), 7.19(d, 1H, J=1.74Hz), 7.57(m, 4H), 7.86(dd, 1H, J=6.39 Hz), 8.03(d, 1H, J=2.13 Hz), 9.11(s, 1H), 9.86(s, 1H); MS (ES)m/z: 585.1 (MH⁺).

EXAMPLE 386N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}butanamide

[0746] The title compound was prepared according to the procedure ofExample 381 as a grey solid; mp 190-201° C.; ¹H NMR (300 MHz, DMSO-d₆)δ0.89 (t, 3 H), 1.50-1.80 (m, 4 H), 2.10-2.40 (m, 4 H), 2.50-2.80 (m, 3H), 3.10-3.30 (m, 2 H), 3.60-3.80 (m, 2 H), 3.90-4.10 (m, 2 H),4.20-4.35 (m, 1 H), 5.80 (d, 1 H), 6.59 (t, 2 H), 6.80-7.00 (m, 2 H),7.40-7.60 (m, 3 H), 8.80 (brs, 1 H), 9.20 (brs, 1 H), 9.70 (s, 1 H),10.65 (s, 1 H), 10.80 (s, 1 H); MS (ES) m/z: 468.0 (MH⁺); HRMS Calcd.for C₂₅H₃₄N₄O₄ (MH⁺): 468.2611. Found: 468.2574.

EXAMPLE 387N-[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]butanamide

[0747] The title compound was prepared according to the procedure ofExample 381 as an off-white solid; mp 194-199° C.; ¹H NMR (300 MHz,DMSO-d₆) δ0.89 (t, 3 H), 1.30-1.45 (m, 2 H), 1.50-1.70 (m, 2 H),1.80-2.00 (m, 2 H), 2.25 (t, 2 H), 2.50-3.00 (m, 5 H), 3.40-3.0 (m, 2H), 4.00-4.20 (m, 3 H), 5.10 (brs, 1 H), 6.70(d, 1 H), 6.82 (d, 2 H),7.00-7.50 (m, 7 H), 8.22 (d, 1 H), 9.60 (s, 1 H), 11.20 (s, 1 H); MS(ES) m/z: 501.0 (MH⁺).

EXAMPLE 388N-[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino-1-piperidinyl)phenyl]-3,4-dimethoxybenzamide

[0748] The title compound, was prepared according to the procedure ofExample 381 as a yellowish solid; mp 77-84° C. ; ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.80 (m, 4 H),3.10-3.40 (m, 1 H), 3.50-3.70 (m, 2 H), 3.82 (s, 3 H) 3.83 (s, 3 H),3.75-3.90 (m, 3 H), 6.58 (d, 1 H), 6.75 (d, 1 H), 6.91 (d, 2 H), 7.06(d, 1 H), 7.40-7.70 (m, 4 H), 8.89 (brs, 1 H), 9.86 (s, 1 H); MS (ES)m/z: 522.0 (MH⁺); HRMS Calcd. for C₂₉H₃₆N₃O₆ (MH⁺); 522.2604. Found:522.2602.

EXAMPLE 389N-[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]3,4-dimethoxybenzamide

[0749] The title compound was prepared according to the procedure ofExample 381 as a yellowish solid; mp 183-191° C.; ¹H NMR (300 MHz,DMSO-d₆) δ1.20-1.45 (m, 2 H), 1.80-2.00 (m, 2 H), 2.50-3.40 (m, 5 H),3.50-3.65 (m, 2 H), 3.73 (s, 3 H), 3.74 (s, 3 H), 4.00-4.20 (m, 3 H),5.10 (brs, 1 H), 6.70 (d, 1 H), 6.90 (d, 1 H), 6.90-7.60 (m, 11 H), 8.25(d, 1 H), 9.87 (s, 1 H), 11.30 (s, 1 H); MS (ES) m/z: 595.1 (MH⁺); HRMSCalcd. for C₃₅H₃₈N₄O₅ (MH⁺): 595.2920. Found: 595.2907.

EXAMPLE 390N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}-amino)-1-piperidinyl]phenyl}-1,3-benzodioxole-5-carboxamide

[0750] The title compound was prepared according to the procedure ofExample 381 as a grey solid; mp 160-169° C. ; ¹H NMR (300 MHz, DMSO-d₆)δ1.30-1.45 (m, 2 H), 1.80-1.95 (m, 2 H); 2.50-2.90 (m, 5 H), 3.50-3.70(m, 2 H), 3.80-4.10 (m, 3 H), 6.25 (s, 2 H), 6.58 (d, 1 H), 6.64 (d, 1H), 6.80-7.00 (m, 5 H), 7.05 (d, 2 H), 7.40-7.60 (m, 5 H), 9.85 (s, 1H), 10.50-10.70 (m, 2 H); MS (ES) m/z: 546.1 (MH⁺); HRMS Calcd. forC₂₉H₃₁N₅O₆ (MH⁺): 546.2353. Found: 546.2343.

EXAMPLE 391N-[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-1,3-benzodioxole-5-carboxamide

[0751] The title compound was prepared according to the procedure ofExample 381 as an off-white solid; mp 217-223° C.; ¹H NMR (300 MHz,DMSO-d₆) δ1.30-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.50-2.90 (m, 5 H),3.50-4.30 (m, 5 H), 6.12 (s, 2 H), 6.70 (d, 1 H), 6.80-7.60 (m, 17 H),9.87 (s, 1 H), 11.30 (s, 1 H); MS (ES) m/z: 579.1 (MH⁺); HRMS Calcd. forC₃₄H₃₅N₄O₅ (MH⁺): 579.2607. Found: 279.2595.

EXAMPLE 3923-Cyclopentyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}propanamide

[0752] The title compound was prepared according to the procedure ofExample 381 as a grey solid; mp 140-144° C.; ¹H NMR (300 MHz, DMSO-d₆)δ1.00-2.00 (m, 15 H), 2.50 (t, 2 H). 2.50-2.90 (m, 5 H), 3.55 (d, 2 H),3.80-4.05 (m, 3 H), 4.90 (brs, 1 H), 6.55 (d, 1 H), 6.63 (d, 1 H),6.80-6.90 (m, 3 H), 7.40 (d, 2 H), 9.60 (s, 1 H), 10.60 (brs, 1 H),10.70 (brs, 1 H); MS (ES) m/z: 522.2 (MH⁺); HRMS Calcd. for C₂₉H₃₉N₅O₄(MH⁺): 522.3080. Found: 522.3091.

EXAMPLE 3933-Cyclopentyl-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-ethyl)amino]-1-piperidinyl}phenyl)propanamide

[0753] The title compound was prepared according to the procedure ofExample 381 as a red solid; mp 82-90° C.; ¹H NMR (300 MHz, DMSO-d₆)δ1.00-2.00 (m, 15 H), 2.30 (t, 2 H), 2.50-2.70 (m, 5 H), 3.45 (brd, 2H), 4.48 (dd, 1 H), 6.70-6.90 (m, 3 H), 6.98 (dd, 1 H), 7.17 (d, 1 H),7.40 (d, 2 H), 9.61 (s, 1 H); MS (ES) m/z: 545.1 (MH⁺); HRMS Calcd. forC₂₈H₄₁N₄O₅S(MH⁺): 545.2798. Found: 545.2788.

EXAMPLE 394N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1,3-benzodioxole-5-carboxamide

[0754] The title compound was prepared according to the procedure ofExample 381 as an off-white solid; mp 104-113° C.; ¹H NMR (300 MHz,DMSO-d₆) δ1.30-1.45 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-2.80 (m, 5 H),2.92 (s, 3 H), 3.55 (d, 2 H), 4.49 (dd, 1 H), 6.15 (s, 2 H), 6.80 (d, 1H), 6.90 (d, 1 H), 6.90-7.10 (m, 3 H), 7.15 (d, 1 H), 7.40-7.60 (m, 4H), 9.80 (s, 1 H); MS (ES) m/z: 569.0 (MH⁺).

EXAMPLE 395 1-Benzhydryl-3-(tert-butyl-dimethyl-silanyloxy)-azetidine

[0755] Tert-butyldimethylsiyl chloride (10.12 g, 42.3mmol) was added toa solution of 1-(diphenylmethyl)-3-hydroxyazetidine(7.65 g, 50.8 mmol)and imidazole(7.2 g; 106 mmol) in anhydrous dimethylforamide(20 mL). Thereaction was stirred at room temperature for 24 hours and then treatedwith water (200 mL). The resultant precipitate was captured on a filterand washed with hot water. The solid was dried under reduced pressure togive 14.1 g of the desired product as a white solid; ¹H NMR (300 MHz,CDCl₃) δ0.06 (s, 6H), 0.84(s, 9H), 2.83 (t, 2H, J=6.42 Hz), 3.52(t, 2H,J=6.09 Hz), 4.21(s, 1H), 4.44(m, 1H), 7.18(m, 2H), 7.23(m, 4H), 7.37(d,4H, J=8.49 Hz); MS (ES) m/z: 354.5 (MH⁺); Anal. Calcd. for C₂₂H₃₁NOSi:C, 74.73; H, 8.84; N, 3.96. Found: C, 74.55; H, 8.75; N, 3.88.

EXAMPLE 396 1-(4-Nitro-phenyl)-azetidin-3-ol

[0756] Ammonium formate (15.1 g, 246 mmol) was added to a solution of1-benzhydryl-3-(tert-butyl-dimethyl-silanyloxy)-azetidine (which wasobtained in Example 395) (8.7 g, 24.6 mmol) and 10%Pd/C (1 g) inmethanol(100 mL). The reaction was stirred for 3 hours at roomtemperature. The solution was passed through celite and concentrated toafford a crude solid. The crude solid was taken up in pyridine (75 mL)and the salts were removed by filtration. 4-Fluoronitrobenzene (2.9 mL,27.1 mmol) was added to the above solution and the reaction was stirredat reflux overnight. Pyridine was removed by vacuum distillation and theresultant crude was treated with water (100 mL), followed by extractionwith ethyl acetate (3×25mL). The organic layers were combined, dried(Na₂SO₄), filtered, and passed through a plug of silica. The solvent wasevaporated and triturated with hexanes to give 3.91 g of the desiredproduct as red solid; ¹H NMR (300 MHz, CDCl₃) δ1.62 (s, 1H), 3.89(m,2H), 4.31 (m, 2H), 4.87(m, 1H), 6.31(d, 2H, J=7.14), 8.09(d, 2H, J=7.14Hz); MS (ES) m/z: 194.8 (MH⁺); Anal. Calcd. for C₉H₁₀N₂O₃: C, 5.67; H,5.19; N, 14.43. Found: C, 55.67; H, 5.05; N, 14.59.

EXAMPLE 397 Methanesulfonic acid 1-(4-nitro-phenyl)-azetidin-3-yl ester

[0757] 1-(4-Nitro-phenyl)-azetidin-3-ol (which was obtained in Example396) (5.0 g, 25.8 mmol) was added to a solution of methanesulfonylchloride (2.2 mL, 28.3 mmol) in dry pyridine (35 mL) and stirred at roomtemperature overnight. Water was added and the resultant precipitate wascaptured on a filter, washed with water, methanol, and hexanes to give3.72 g of the desired product as an orange solid; ¹H NMR (DMSO-d₆) δ3.35(s, 3H), 4.15(m, 3H), 4.45(m, 2H), 5.48(m, 1H), 6.53(d, 2H, J=9.12 Hz),8.09(d, 2H, J=9.12 Hz); MS (ES) m/z: 273.5 (MH⁺); Anal. Calcd. forC₁₀H₁₂N₂O₅S: C, 44.11; H, 4.44; N, 10.29. Found: C, 44.50; H, 4.48; N,10.64.

EXAMPLE 398 Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine

[0758] Methanesulfonic acid 1-(4-nitro-phenyl)-azetidin-3-yl ester(which was obtained in Example 397) (14.32 g, 52.6 mmol) was added toneat benzyl amine (56 mL, 526 mmol) and stirred at 100° C. for 2 days.Water (200 mL) was added and the resultant precipitate was collected andpartitioned between ethyl acetate and saturated aqueous NaHCO₃. Theaqueous layer was washed with ethyl acetate (2×50 mL). The organicextract was dried over anhydrous sodium sulfate, filtered, andconcentrated. The solid was washed with diethyl ether and dried to give12.1 g of the desired product as an orange solid; ¹H NMR (300 MHz,CDCl₃) δ1.66 (brs, 1H), 3.72(m, 2H), 3.82 (s, 2H, 3.89(m, 1H), 4.19(t,2H, J=7.77 Hz), 6.29(d, 2H, J=9.12 Hz), 7.34(m, 5H), 8.07(d, 2H, J=9.18Hz); MS (ES) m/z: 283.8 (MH⁺); Anal. Calcd. for C₁₆H₁₇N₃O₂: C, 67.83; H,6.05; N, 14.83. Found: C, 67.59; H, 6.04; N, 14.79.

EXAMPLE 399(2S)-1-{Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amino}-3-(9H-carbazol-4-4-yloxy)-propan-2-ol

[0759] Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine (which wasobtained in Example 398) (1.95 g, 6.87 mmol) and(2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (Berridge et al., Int. J.Radial. Appl. Instrum., 1992, 563) (1.64 g, 6.87 mmol) was stirred atreflux in anhydrous methanol for 24 hours. Methanol was removed in vacuoand the desired product was isolated using silica gel flashchromatography to give 3.01 g of product as a yellow solid; ¹H NMR (300MHz, CDCl₃) δ2.90 (m, 2H), 3.04(s, 1H), 3.85 (m, 3H), 3.98(m, 3H),4.23(m, 3H), 6.01(d, 2H, J =7.26 Hz), 6.61(d, 1H, J=8.10 Hz), 7.06(d,1H, J=8.04 Hz), 7.17(t, 1H, J=2.14 Hz), 7.34(m, 7H), 7.97(d, 2H, J=9.12Hz), 8.14(t, 2H, J=8.79 Hz); MS (ES) m/z: 522.9 (MH⁺); Anal. Calcd. forC₃₁H₃₀N₄O₄: C, 71.25; H, 5.79; N, 10.72. Found: C, 70.77; H, 6.17; N,9.61.

EXAMPLE 400(2S)-1-{Benzyl-[1-(4-nitro-phenyl-azetidin-3-yl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol

[0760] Benzyl-[1-(4-nitro-phenyl)-azetidin-3-yl]-amine (which wasobtained in Example 398) (2.07 g, 7.34 mmol) and(2S)-2-(4-benzyloxy-phenoxymethyl-oxirane (EP 0 714 883) (2.07 g, 6.99mmol) were stirred at reflux in anhydrous methanol for 24 hours.Methanol was removed in vacuo and the desired product was isolated usingsilica gel flash chromatography to give 3.01 g of product as a yellowsolid; ¹H NMR (300 MHz, CDCl₃) δ2.74 (m, 2H), 2.95(brs, 2H), 3.90 (m,2H), 3.94(m, 4H), 4.01(m, 2H), 4.05(q, 2H, J=7.11 Hz), 5.01(s, 2H),6.28(d, 2H, J=5.28 Hz), 6.82(d, 2H, J=4.35 Hz), 6.89(d, 2H, J=4.35 Hz),7.34(m, 10H), 8.08(d, 2H, J=5.34 Hz); MS (ES) m/z: 540.0 (MH⁺); Anal.Calcd. for C₃₂H₃₃N₃O₅: C, 71.23; H, 6.16; N, 7.79. Found: C, 70.68; H,6.34; N, 7.61.

EXAMPLE 401(2S)-1-{[1-(4-Amino-phenyl)-azetidin-3-yl-benzyl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol

[0761] Sodium hydrosulfite (3.0 g, 17.2 mmol) was added to aheterogeneous solution of(2S)-1-(benzyl-[1-(4-nitro-phenyl-azetidin-3-yl]-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol(which was obtained in Example 400) (1.0 g, 1.72 mmol), sodiumbicarbonate (1.5 g, 1.72 mmol) in acetonitrile (15 mL), methanol (35 mL)and water (10 mL). This reaction was stirred at 60° C. overnight. Solidswere removed by filtration. The mother liquor was concentrated and theresultant crude was taken up in water followed by extraction with ethylacetate (3×20 mL). The organic extract was dried over anhydrous sodiumsulfate, passed through a plug of silica, and concentrated to give 0.89g of the desired product as a brown gum; ¹H NMR (300 MHz, CDCl₃)δ2.66(m, 2H), 3.13(brs, 2H), 3.56 (m, 4H), 3.77(m, 2H), 3.90(m, 4H),4.99(s, 2H), 6.33(d, 2H, J=4.80 Hz), 6.59(d, 2H, J=6.78 Hz), 6.81(d, 2H,J=9.21 Hz), 6.86(d, 2H, J=6.75), 7.36(m, 10H); MS (ES) m/z: 510.0 (MH⁺).

EXAMPLE 402N-Acetyl-N-[4-(3-{benzyl-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl]-acetamide

[0762] Acetic anhydride (0.09 mL, 0.93 mmol) was added to a solution of(2S)-1-{[1-(4-amino-phenyl)-azetidin-3-yl]-benzyl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol(which was obtained in Example 401) (0.37 g, 0.727 mmol) andN,N-dimethylaminopyridine (catalytic amount) in anhydrous methylenechloride (7 mL). The reaction was stirred at room temperature overnight.The solution was then treated with water (30 mL) followed by extractionwith ethyl acetate (3×30 mL). The organic extract was dried withanhydrous sodium sulfate, filtered and concentrated to afford a crudesolid. The desired product was isolated using silica gel flashchromatography to give 0.41 g of an off-white solid; ¹H NMR (300 MHz,CDCl₃) δ2.05(s, 3H), 2.12(s, 3H), 2.75(m, 1H), 2.93(m, 1H), 3.49(m, 2H),3.65(d, 2H, J=14 Hz), 3.75(m, 1H), 3.88(m, 2H), 4.01(d, 2H, J=4.23 Hz),5.01(s, 2H), 5.18(m, 1H), 6.36(d, 2H, J=8.4 Hz), 6.79(d, 2H, J=6.78 Hz),6.89(d, 2H, J=6.78 Hz), 7.32(m, 8H), 7.38(m, 4H). MS(ES) m/z: 594.1(MH⁺).

EXAMPLE 403N-[4-(3-{Benzyl-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl]-4-butoxy-benzenesulfonamide

[0763] 4-Butoxybenzenesulfonyl chloride (0.20 g, 0.79 mmol) was added toa solution of(2S)-1-{[1-(4-amino-phenyl)-azetidin-3-yl]-benzyl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol(which was obtained in Example 401) (0.37 g, 0.727 mmol) andtriethylamine (0.56 mL, 3.99 mmol) in anhydrous methylene chloride (7mL). The reaction was stirred at room temperature overnight. Thesolution was then treated with water (30 mL) followed by extraction withethyl acetate (3×30 mL). The organic extract was dried with anhydroussodium sulfate, filtered and concentrated to afford a crude solid. Thedesired product was isolated using silica gel flash chromatography togive 90 mg of an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ0.99(t, 3H,J=5.04 Hz), 1.47(m, 2H), 1.78(m, 2H), 2.69(m, 2H), 3.08(brs, 1H),3.65(m, 3H), 3.78(m, 2H), 3.87(m, 4H), 3.95(t, 2H, J=6.45 Hz), 5.01 (s,2H), 6.01(s, 1H), 6.29(d, 2H, J=8.73 Hz), 6.86(m, 10H), 7.35(m, 8H),7.56(d, 2H, J=8.94 Hz). MS (ES) m/z: 722.1 (MH⁺); Anal. Calcd. forC₄₂H₄₇N₃O₆S: C, 69.88; H, 6.56; N, 5.82. Found: C, 68.91; H, 6.38; N,5.55.

EXAMPLE 404N-[4-(3-{Benzyl-[3-(9H-carbazol-4-yloxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl-acetamide

[0764] The title compound was prepared according to the procedure ofExample 403 as an off-white solid; ¹H NMR (DMSO-d₆) δ1.95(s, 3H),2.64(m, 1H), 2.82(m, 1H), 3.32(s, 2H), 3.47(m, 2H), 3.67(m, 4H), 4.12(m,2H), 5.07(d, 1H, J=4.5 Hz), 6.15(d, 2H, J=8.7 Hz), 6.09(d, 1H, J=8.79Hz), 6.65(d, 1H, J=7.95 Hz), 7.07(m, 2H), 7.26(m, 10H), 7.46(d, 1H,J=7.71 Hz), 8.18(d, 1H, J=7.71 Hz), 9.57(s, 1H), 11.25(s, 1H); MS (ES)m/z: 535.1; (MH⁺); HRMS found for C₃₃H₃₄N₄O₃: 534.2643

EXAMPLE 405N-[4-(3-{Benzyl-[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propyl]-amino}azetidin-1-yl)-phenyl]-4-butoxy-benzenesulfonamide

[0765] The title compound was prepared according to the procedure ofExample 403 as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ0.95(t, 3H,J=4.95 Hz), 1.45(m, 2H), 1.74(m, 2H), 2.83(m, 2H), 3.22(brs, 1H),3.61(m, 3H), 3.79(s, 1H), 3.84(m, 3H), 3.93(t, 2H, J=7.29 Hz), 4.15(m,2H), 6.15(d, 2H, J=8.7 Hz), 6.24(s, 1H), 6.59(d, 2H, J=6.99 Hz), 6.84(m,4H), 7.04(d, 1H, J=8.01 Hz), 7.18(m, 2H), 7.37(m, 2H), 7.54(d, 2H,J=7.02 Hz), 8.17(s, 1H, 8.18(s, 1H); MS (ES) m/z: 705.1 (MH⁺).

EXAMPLE 406.N-[4-(3-{Benzyl-[3-(9H-carbazol-4-yloxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl-3,4-dimethoxy-benzenesulfonamide

[0766] The title compound was prepared according to the procedure ofExample 403; ¹H NMR (300 MHz, CDCl₃) δ2.82(m, 2H), 3.18(brs, 1H),3.61(m, 3H), 3.75(s, 3H), 3.79(m, 1H), 3.89(s, 3H), 3.93(m, 2H), 4.17(m,3H), 6.12(s, 1H), 6.21(d, 2H, J=8.7 Hz), 6.63(d, 1H, J=7.95 Hz), 6.83(m,3H), 7.06(m, 3H), 7.25(m, 1H), 7.28(m, 2H), 7.39(m, 1H), 8.15(s, 1H),8.21(d, 1H, J=7.8 Hz); MS (ES) m/z: 693.1 (MH⁺); HRMS found forC₃₉H₄₀N₄O₆S: 693.2731.

EXAMPLE 407N-{4-[4-(3-{Benzyl-[3-(9H-carbazol-4-yloxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide

[0767] The title compound was prepared according to the procedure ofExample 403; ¹H NMR (300 MHz, CDCl₃) δ2.17(s, 3H), 2.85(m, 2H), 3.59(m,3H), 3.68(m, 1H), 3.80(m, 3H), 4.19(m, 3H), 6.13(d, 2H, J=8.67 Hz),6.06(d, 1H, J=7.95 Hz), 6.86(d, 2H, J=8.64 Hz), 7.08(d, 1H, J=8.07 Hz),7.14(t, 1H, J=7.5 Hz), 7.31(m, 8H), 7.59(q, 4H, J=7.71 Hz), 8.22(d, 1H,J=7.71 Hz), 8.51(s, 1H), 9.50(s, 1H), 79(s, 1H); MS (ES) m/z: 690.1(MH⁺); HRMS found for C₃₉H₃₉NO₅S: 690.2777.

EXAMPLE 408N-[4-(3-{Benzyl-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl]-3,4-dimethoxy-benzenesulfonamide

[0768] The title compound was prepared according to the procedure ofExample 403; ¹H NMR (300 MHz, CDCl₃) δ2.69(m, 2H), 3.06(brs, 1H),3.63(m, 3H), 3.78(s, 3H), 3.87(m, 3H), 3.91(s, 3H), 3.93(m, 3H), 5.01(s, 2H), 6.05(s, 1H), 6.29(d, 2H, J=9.81 Hz), 6.82(m, 10H), 7.06(d, 1H),7.56(d, 2H, J=6.94 Hz), 7.34(m, 10H). MS (ES) m/z: 710.1 (MH⁺); HRMSfound for C₄₀H₄₃N₃O₇S: 710.2899.

EXAMPLE 409N-{4-[4-(3-{Benzyl-[3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenylsulfamoyl]-phenyl)-acetamide

[0769] The title compound was prepared according to the procedure ofExample 403; ¹H NMR (300 MHz, CDCl₃) δ2.17(s, 3H), 2.67(m, 2H),3.15(brs, 1H), 3.62(m, 3H), 3.78(m, 2H), 3.88(m, 4H),5.01(s, 2H),6.26(m, 3H), 6.87(m, 6H), 7.34(m, 5H), 7.40(m, 3H), 7.52(d 5H). MS (ES)m/z: 707.1 (MH⁺); HRMS found for C₄₀H₄₂N₄O₆S: 707.2901.

EXAMPLE 410N-Acetyl-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)]propyl]amino}-1-azetidinyl)phenyl]acetamide

[0770] Ammonium formate (0.57 g, 9.1 mmol) was added to a solution ofN-acetyl-N-[4-(3-{benzyl-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propyl]-amino}-azetidin-1-yl)-phenyl]-acetamide(which was obtained in Example 402) (0.25 g, 0.45 mmol) and 10% Pd/C(0.05 g) in dry methanol (7 mL). The reaction was stirred at roomtemperature overnight. The solution was passed through a pad of celiteand then was concentrated. The crude solid was treated with saturatedaqueous NaHCO₃ (30 mL) followed by extraction with ethyl acetate (3×2mL). The organic extract was dried over anhydrous sodium sulfate,filtered, and evaporated to afford 0.18 g of the desired product as awhite solid; ¹H NMR (300 MHz, CDCl₃) δ2.05 (s, 6H), 2.61(s, 1H), 2.75(m,2H), 3.49(m, 2H), 3.75(m, 1H), 3.85(d, 2H, J=7.13 Hz), 4.02(t, 2H, J=5.3Hz), 4.12(q, 1H), 6.32(d, 2H, J=11.12 Hz), 6.90(d, 2H, J=11.32 Hz),6.55(q, 4H, J=4.6 Hz), 7.53(d, 2H, J=7.02 Hz), 7.61(brs, 1H); MS (ES)m/z: 414.0(MH⁺).

EXAMPLE 4114-Butoxy-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide

[0771] The title compound was prepared according to the procedure ofExample 410 as a dark blue solid; ¹H NMR (300 MHz, DMSO-d₆CDCl₃) δ0.97(t, 3H, J=7.41 Hz), 1.48 (m, 2H), 1.78(m, 2H), 2.58(m, 1H), 2.75(m, 2H),3.49(m, 2H), 3.75(m, 1H), 3.85(d, 2H), 3.97(t, 2H, J=5.7 Hz), 4.02(t,2H, J=7.41 Hz), 4.12(q, 1H), 6.26(d, 2H, J=11.67), 6.75(s, 4H), 6.84,(d, 2H, J 5.1 Hz), 6.90(d, 2H, J=11.76 Hz), 7.53(d, 2H, J=6.99 Hz),8.35(brs, 1H); 8.60(brs, 1H); MS (ES) m/z: 542.0(MH⁺); HRMS found forC₂₈H₃₅N₃O₆S: 542.2362.

EXAMPLE 412N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0772] The title compound was prepared according to the procedure ofExample 410 as a blue solid; ¹H NMR (300 MHz, DMSO-d₆/CDCl₃) δ2.58(m, 1H), 2.76(m, 2H), 3.41 (s, 1H), 3.49(m, 2H), 3.71(m, 1H), 3.80(s, 3H),3.89(s, 3H), 3.90(d, 2H, J=3.39 Hz), 4.12(q, 1H, 6.26(d, 2H, J =5.01Hz), 6.75(s, 4H). 6.83(d, 1H, J=8.49 Hz), 6.90(d, 1H, J=8.73 Hz),7.16(d, 1H, J=2.07 Hz), 7.29(dd, 1H), 8.35(brs, 1H), 8.60(brs, 1H); MS(ES) m/z: 530.0(MH⁺); HRMS found for C₂₆H₃₁N₃O₇S: 530.1991.

EXAMPLE 413N-(4-{[4-(3-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)anilino]-sulfonyl}phenyl)acetamide

[0773] The title compound was prepared according to the procedure ofExample 410 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.06, (s 3H),2.53(m, 1H), 2.61(m, 2H), 3.35(m, 2H), 3.58(m, 1H), 3.78(m, 3H), 3.85(t,2H), 4.89(brs, 1H), 6.26(d, 2H, J=8.7 Hz), 6.65(d, 2H, J=6.6 Hz),6.72(d, 2H, J=2.4 Hz), 6.93(d, 2H, J=1.8 Hz), 7.54(d, 2H, J=9.0 Hz),7.83(d, 2H, J=8.8 Hz) 8.87(s, 1H), 8.45(brs, 1H), 10.26(s, 1H); MS (ES)m/z: 527.1(MH⁺); HRMS found for C₂₆H₃₀N4O₆S: 527.1975.

EXAMPLE 4144-Butoxy-N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide

[0774] The title compound was prepared according to the procedure ofExample 410 as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ0.97 (t, 3H,J=7.47 Hz), 1.48 (m, 2H), 1.78(m, 2H), 3.01(m, 2H), 3.47(m, 2H), 3.95(t,2H, J=5.94 Hz), 4.04(d, 2H, J=6.66), 4.29(m, 2H), 4.32(m, 1H), 6.15(brs,1H), 6.26(d, 2H, J=8.73 Hz), 6.67(d, 1H, J=7.95 Hz), 6.83, (d, 2H, J=2.7Hz), 7.07(d, 1H, J=8.01 Hz), 7.22(m, 2H), 7.32(t, 2H, J=8.04 Hz),7.41(m, 2H), 7.57(d, 2H, J=5.04 Hz), 8.13(brs, 1H), 8.25(d, 1H, J=7.77Hz); MS (ES) m/z: 615.1(MH⁺); HRMS found for C₃₄H₃₈N₄O₅S: 615.2656.

EXAMPLE 415N-[4-(3-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]acetamide

[0775] The title compound was prepared according to the procedure ofExample 410 as a dark brown solid; ¹H NMR (300 MHz, CDCl₃) δ2.05(s, 3H),3.01 (m, 2H), 3.47(m, 2H), 3.95(m, 2H), 4.04(m, 2H), 4.29(m, 2H),6.35(d, 1H, J=6.3 Hz), 6.69(d, 1H, J=6.9 Hz), 7.04, (brs, 1H), 7.21(m,1H), 7.29(m, 2H), 7.32(m, 2H), 7.41(m, 2H), 7.30(m, 2H), 8.10(brs, 1H),8.27(m, 1H); MS (ES) m/z: 445.1(MH⁺).

EXAMPLE 416N-[4-(3-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide

[0776] The title compound was prepared according to the procedure ofExample 410 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.76(m,2H), 3.18(d, 2H, J=5.22 Hz), 3.72(s, 3H), 3.78(s, 3H), 3.93(t, 2H,J=6.96 Hz), 4.02(m, 1H), 4.14(m, 2H), 4.19(m, 1H), 5.11(d, 1H, J=4.92Hz), 6.2(d, 2H, J=9.0 Hz), 6.69(d, 2H, J=8.1 Hz), 6.85(d, 2H, J=8.7 Hz),7.13(m, 2H), 7.17(m, 2H), 7.33(m, 2H),7.43(d, 2H, J=8.1 Hz), 8.21 (d, 1H, J=7.8 Hz), 9.45(brs, 1H); MS (ES) m/z: 603.0(MH⁺); HRMS found forC₃₂H₃₄N₄O₆S: 603.2296.

EXAMPLE 417N-(4-{[4-(3-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide

[0777] The title compound was prepared according to the procedure ofExample 410 as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.06(s,3H), 2.71(m, 2H), 3.40(m, 2H), 3.68(m, 1H), 3.93 (t, 2H, J=6.93 Hz),4.02(m, 2H), 4.13(m, 1H), 5.09(d, 1H, J=4.95 Hz), 6.25(d, 2H, J=8.7 Hz),6.47(d, 1H, J=8.7 Hz), 6.81(d, 2H, J=8.7 Hz), 7.13(m, 2H), 7.27(m, 2H),7.46(d, 2H, J=8.1 Hz), 7.68(d, 2H, J=9.0 Hz), 8.21(d, 1H, J=7.8 Hz),9.50(brs, 1H), 10.27(brs, 1H), 11.24(s, 1H); MS (ES) m/z: 600.0(MH⁺);HRMS found for C₃₂H₃₃N₅O₅S: 600.2280.

What is claimed is:
 1. A compound of formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per. alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalky of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl; alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino, of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms,

R⁵ is Aa is (i) an amino acid, wherein the nitrogen of amino acidattached to the adjacent carbonyl of R⁵; or (ii) an alkyl ester of anamino acid, wherein the nitrogen of amino acid attached to the adjacentcarbonyl of R⁵, and the alkyl moiety of the alkyl ester contains 1-6carbon atoms; Y and Z are each, independently, NR⁷, O, or S; X¹ and X²are each, independently, CO or SO₂; R⁶, R⁷, and R⁸ are each,independently, hydrogen; alkyl of 1-6 carbon atoms optionallysubstituted by R¹¹, R¹², and R¹³; alkenyl of 2-7 carbon atoms optionallysubstituted by R¹¹, R¹², and R¹³; alkynyl of 2-7 carbon atoms optionallysubstituted with R¹¹; cycloalkyl of 3-8 carbon atoms optionallysubstituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11 carbon atomsoptionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of 1-6 carbonatoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Ar optionallysubstituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ are contained on acommon nitrogen, they may be taken together to form a saturated 5-7membered heterocycle that is optionally substituted with R¹¹; R⁹ and R¹⁰are each, independently, alkyl optionally substituted by R¹¹, R¹², andR¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵; Ar fused to acycloalkyl ring of 3-8 carbon atoms, and optionally mono-, di-, ortri-substituted by R¹⁵; Het optionally mono-, di-, or tri-substituted byR¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkyl of 1-6 carbonatoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbon atomsin the alkyl moiety, Ar optionally substituted with R¹⁴, Het optionallysubstituted with R¹⁴, hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo,—CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkyl moiety has 1-6carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkylof 1-6 carbon atoms, —NHSO₂-alkyl of 1-6 carbon atoms, —NHSO₂—Ar, or—NHSO₂—Het; or when R¹¹ and R¹² are contained on a common carbon atom ofan alkyl moiety, they may be taken together to form a spiro cycloalkylring of 3-8 carbon atoms; R¹⁴ is halogen, alkoxy of 1-6 carbon atoms,alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, hydroxy, acyl of 2-7 carbon atoms, -SO₂-alkyl of 1-6carbon atoms, —CO₂-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of3-13 carbon atoms; R¹⁵ is (a) hydroxy, halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶,—SR¹⁶, triflouromethyl, alkyl of 1-6 carbon atoms, —SO₂R¹⁷,—O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains 1-6 carbon atoms,—CO₂R¹⁷, ——OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or —NR¹⁶CO₂R¹⁶; or(b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR16; triflouromethyl; alkyl of 1-6carbon atoms; —SO₂R¹⁷ ; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷; —COR¹⁷;—NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R17isR¹⁶or NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10 ringatoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein A is Ar orHet; X is —OCH₂— or a bond; T¹ is (CH₂)_(m); T² is (CH₂)_(n); T is abond, alkyl of 1-6 carbon atoms optionally substituted with R¹¹, alkenylof 2-7 carbon atoms optionally substituted with R¹¹, or alkoxyalkyl of1-6 carbon atoms per alkyl moiety; R¹, R², and R³ are each,independently, hydrogen, alkyl of 1-6 carbon atoms, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, acyloxy of 2-7carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms,arylsulfonylamino, —CO₂-alkyl of 1-6 carbon atoms, or Ar optionallysubstituted with R¹¹; R⁴ is hydrogen or halogen; R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and x² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; cycloalkyl of3-8 carbon atoms optionally substituted by R¹¹, R¹², and R¹³;bicycloalkyl of 7-11 carbon atoms optionally substituted by R¹¹, R¹²,and R¹³; —CO₂-alkyl of 1-6 carbon atoms; Het optionally substituted byR¹¹, R¹², or R¹³; or Ar optionally substituted by R¹¹, R¹², and R¹3; orwhen R⁶ and R⁷ are contained on a common nitrogen, they may be takentogether to form a saturated 5-7 membered heterocycle that is optionallysubstituted with R¹¹; R⁹ and R¹⁰ are each, independently, alkyloptionally substituted by by R¹¹, R¹², and R¹³; Ar optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, or tri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently,alkyl of1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6 carbonatoms in the alkyl moiety, Ar optionally substituted with R¹⁴, Hetoptionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbon atoms,Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂-Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂-Ar, or —NHSO₂-Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, hydroxy,acyl of 2-7 carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of1-6 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is(a) halogen, —CN, —OR¹⁶, triflouromethyl, alkyl of 1-6 carbon atoms,—SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains 1-6 carbonatoms, —CO₂R¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷; or (b) alkyl of 1-6 carbon atomsmono-, or di-substituted with halogen; —NR¹⁶COR¹⁷; Ar which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;or Het which may be optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; (c) Het optionally mono- or di-substituted by R¹⁶,—OR¹⁶, —NR¹⁶R¹⁶, or halogen; or (d) Ar optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen,alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-14 carbon atoms, benzyl,Ar or Het, wherein the Ar or Het moieties may be optionally mono-, di-,or tri- substituted with halogen, nitro, alkylamino of 1-6 carbon atoms,dialkylamino of 1-6 carbon atoms per alkyl moiety, trifluoromethyl,alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6carbon atoms, —CO₂H, —CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6carbon atoms; R¹⁷ is R¹⁶ or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclicheterocycle of 5-10 ring atoms, having 1-4 heteroatoms selected fromoxygen, nitrogen, and sulfur; wherein the heterocycle may be saturated,unsaturated, or partially unsaturated; and may be optionally fused to aphenyl ring; Ar is an aromatic ring system containing 1-2 carbocyclicaromatic rings having 6-10 carbon atoms; m=1-2; n=1-2; or apharmaceutically acceptable salt thereof.
 3. The compound of claim 1,which is a)N-[5-((1R)-2-{1-[4-(3,5-dioxo-[1,2,4]oxadiazolidin-2-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;b)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-_1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid tert-butyl-ester; c)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid; d)5-[[4-[4-[[(R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-1-piperidinyl]phenyl]methyl]-2,4-dioxo-3-thiazolidineaceticacid ethyl-ester; e)5-(3-fluoro-4-[4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;f)5-(3-bromo-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;g)5-(3-fluoro-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;h)N-[5-(2-{1-[2-bromo-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;i)N-[5-(2-(1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-2-fluoro-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;j)5-(4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene)-2-thioxo-thiazolidin-4-one;k)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzyl}-thiazolidin-2,4-dione;5-(4-{4-[(2S)-3-(4-benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidin-1}-benzyl)-thiazolidine-2,4-dione;m)5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;n)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazolidine-2,4-dione;o)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;p)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;q)5-(4-{4-[2-(3-chloro-phenyl)-(2R)-2-hydroxyethylamino}-piperidin-1-yl}benzyl)-thiazolidine-2,4-dione;r)5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;s)5-(4-}4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;t)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-thioxo-thiazolidin-4-one;u)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazolidine-2,4-dione;v)N-[5-((2R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;w)N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;x)5-(4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-imidazolidine-2,4-dione-piperidin-1-yl}-benzyl)-imidazolidine-2,4-dione;y)N-[5-(2-{1-[4-(2,5-dioxo-imidazolidin-4-ylmethyl)-phenyl]-piperidin-4-ylamino)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;z)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;aa)4-((2S)-2-hydroxy-3-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;bb)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-imino-4-oxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;cc)5-(4-{4-[(2S)-2-hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl)-benzyl)-thiazolidine-2,4-dione;dd)N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide;ee)N-[5-((2S)-3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide;ff) (R)-propane-2-sulfonic acid[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-amide;gg)N-[2-chloro-5-((1R)-2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino)-1-hydroxy-ethyl)-phenyl]-methanesulfonamide;hh)N-(5-{(1R)-2-[(1-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidin-4-yl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)benzenesulfonamide;ii)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(1H-tetrazol-5-yl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;jj) ethyl[5-(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]acetate;kk)[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1H-tetraazol-1-yl]aceticacid; ii)[5-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2H-tetraazol-2-yl]aceticacid; mm)5-{4-[4-({(2S)-2-hydroxy-2-[2-(trifluoromethyl)-1,3-thiazol-4-yl]ethyl}amino)piperidine-1-yl]benzyl}-1,3-thiazolidine-2,4-dione;nn)5-{4-[4-({(2S)-2-[3-(3,4-dichlorophenyl)isoxazol-5-yl]-2-hydroxyethyl}amino)piperidin-1-yl}benzyl}-1,3-thiazole-2,4-dione;00)N-(4-{(1R)-2-[(1-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenyl}piperidine-4yl)amino]-1-hydroxyethyl)}phenyl)methanesulfonamide;pp)5-[4-(4-{[4-(2S)-2-(3-bromoisoxazol-5-yl)-2-hydroxyethyl]amino}piperidine-1-yl)benzyl]-1,3-thiazolidine-2,4-dione;qq)5-(4-{4-[(2S)-2-hydroxy-3-(pyridin-3-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;rr)5-(4-{4-[(2S)-2-hydroxy-3-(6-methyl-pyridin-3-yloxy)-propylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dione;ss)5-{4-[4-((2S)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione;tt)5-(4-{4-[(2S)-2-(6-amino-pyridin-3-yl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzyl)-thiazolidine-2,4-dionehydrochloride; uu)5-{4-[4-((2R)-2-hydroxy-2-pyridin-3-yl-ethylamino)-piperidin-1-yl]-benzyl}-thiazolidine-2,4-dione;vv)N-[5-(2-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-pyridin-2-yl]-methanesulfonamide;ww)5-(3-{1-[4-(2,4-dioxo-thiazolidin-5-ylmethyl}-2-fluoro-phenyl]-piperidin-4-ylamino-(2S)-2-hydroxy-propoxy)-2-methyl-1H-indole-3-carboxylicacid ethyl ester; xx)N-[(2R)-2-hydroxy-5-(1-hydroxy-2-{1-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3yl)-phenyl]-piperidin-4-ylamino)-ethyl)-phenyl]-methanesulfonamide;yy)4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzoicacid ethyl ester; zz){4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester; aaa){4-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzoicacid ethyl ester hydrochloride; bbb)(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-aceticacid; ccc)3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid ethyl ester; ddd)3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-phenyl)-propionicacid; eee)(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-benzyloxy)-aceticacid; fff)4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoicacid; ggg)3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-phenyl)-propionicacid ethyl ester; hhh)2-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-benzylidene)-malonicacid diethyl ester; iii)2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-malonic acid monoethyl ester;jjj)4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzamide;kkk)N-benzyloxy-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-benzamide;iii) diethyl(2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioate;mmm) ethyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]propanoate;nnn)(2S)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]pentanedioicacid; ooo)N-(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)-beta-alanine;ppp) ethyl[(4-{4-[((2R)-2-hydroxy-2-(4hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate;qqq)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]aceticacid; rrr)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid ethyl ester; sss)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid; ttt)1-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-pyrrolidine-(2S)-2-carboxylicacid methyl ester; uuu)1-(4-{4-[(2R)-2-hydroxy-2(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)pyrrolidine-(2S)-2-carboxylicacid; vvv)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-methyl-butyricacid ethyl ester; www)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl)-benzoylamino)-3-methyl-butyricacid; xxx)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid methyl ester; yyy)(2S)-2-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-3-phenyl-propionicacid; zzz) methyl1-[(4-(4-[((2R)-2-hydroxy-2-(4-hydroxy-3-piperidinylbenzoyl)amino]cyclopropanecarboxylate;aaaa)[butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoyl)-amino]-aceticacid ethyl ester; bbbb) methyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}benzoyl)amino]acetate;cccc)(2S)-2-(4-{4-[2hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzoylamino)-4-methyl-pentanoicacid methyl ester; dddd)(2E)-3-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-acrylicacid; eeee)4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]benzamide;ffff)4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-sulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-l}ethyl)amino]-1-piperidinyl}-N-[(3S)-2-oxoazepanyl]benzamide;gggg)N-butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-N-(1H-tetraazol-5-ylmethyl)benzamide.hhhh)N-{4-[4-(2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-phenyl}-4-methoxy-benzenesulfonamide;iiii)N-(4-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl}-phenyl)-4-methoxy-benzenesulfonamide;jjjj)N-[4-(4-{4-[2-hydroxy-2-(3-hydroxy-phenyl)-ethylamino]-piperidin-1-yl-phenylsulfamoyl)-phenyl]-acetamide;kkkk)N-(4-{4-[4-((2R)-2-hydroxy-2-phenyl-ethylamino)-piperidin-1-yl]-phenylsulfamoyl}-phenyl)-acetamide;llll)N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;mmmm)N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;nnnn)N-[4-(4-{[(2R)-2-hydroxy-2-phenylethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;oooo)N-(4-{[4-(4-{[2-hydroxy-3-(4-methoxyphenoxy)propyl]amino)-1-piperidinyl)anilino]sulfonyl)phenyl)acetamide;pppp)N-(4-{[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;qqqq)N-(4-{[2-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;rrrr)N-(4-{[2-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;ssss)N-[4-(4-{[(2R)-2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-methoxybenzenesulfonamide;tttt)N-(4-{[4-(4-{[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;uuuu)N-(4-{[4-(4-{[2-(2,4-dihydroxyphenyl)-2-hydroxyethyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;vvvv)N-(4-{[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;wwww)N-{4-[(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide;xxxx)4-{[(hexylamino)carbonyl]amino}-N-[4-(4-{[2-hydroxy-2-(6-methyl-3-pyridinyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;yyyy)N-(4-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;zzzz)5-[2-({1-[4-({[4-(acetylamino)phenyl]sulfonyl}amino)phenyl]-4-piperidinyl}amino)-1-hydroxyethyl]-1H-indole-7-carboxamide;aaaaa) N-[4-({4-[4-({(2S)-2-hydroxy3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide;bbbbb)4-{[(hexylamino)carbonyl]amino}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;ccccc)4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;ddddd)4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;eeeee)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-5-(2-pyridinyl)-2-thiophenesulfonamide;fffff)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;ggggg)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-dimethoxybenzenesulfonamide;hhhhh)4-butoxy-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;iiiii)N-(4-{[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino)-1-piperidinyl)anilino]sulfonyl}phenyl)acetamide;jjjjj) 5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3-methyl-1-benzothiophene-2-sulfonamide;kkkkk) 4-cyano-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;lllll)4-cyano-N-[(4-cyanophenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;mmmmm)3-bromo-5-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide;nnnnn)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl)-5-(3-isoxazolyl)-2-thiophenesulfonamide;ooooo)4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetraazol-1-yl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;ppppp)4-butoxy-N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino)-1-piperidinyl}phenyl]benzenesulfonamide;qqqqq)N-[4-(4-{[3-(9H-carbazol-4-yloxy)-(2S)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-4-{[(hexylamino)carbonyl]amino}benzenesulfonamide;rrrrr)N-{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenyl}acetamide;sssss)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;ttttt)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-5-(2-pyridinyl)-2-thiophenesulfonamide;uuuuu)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-5-(2-pyridinyl)-2-thiophenesulfonamide;vvvvv)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide;wwwww)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide;xxxxx)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-octanesulfonamide;yyyyy)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-octanesulfonamide;zzzzz)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;aaaaaa)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}1-piperidinyl)phenyl]-5-{[5-(trifluoromethyl)-2-pyridinyl]sulfonyl}-2-thiophenesulfonamide;bbbbbb)4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;cccccc)4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;dddddd)N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide;eeeeee)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-1-octanesulfonamide;ffffff)4-{[(hexylamino)carbonyl]amino}-N-(4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl)benzenesulfonamide;gggggg)N-{4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1-butanesulfonamide;hhhhhh)N-[4-({4-[4-({(2S)-2-hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolinyl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenyl]acetamide;iiiiii)N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}phenyl)-,4-dimethoxybenzenesulfonamide;jjjjjj)N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl)phenyl)-1-butanesulfonamide;kkkkkk)4-{[(hexylamino)carbonyl]amino}-N-(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy}propyl)amino]-1-piperidinyl}phenyl)benzenesulfonamide;llllll)N-[4-(4-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-1-piperidinyl)phenyl]-4-([(hexylamino)carbonyl]amino}benzenesulfonamide;mmmmmm) ethyl{4-[(4-{4-[((2S)-2-hydroxy-3-{4-hydroxy-3-[(methylsulfonyl)amino]phenoxy)propyl)amino]1-piperidinyl}anilino)sulfonyl]phenyl}acetate;nnnnnn) methyl}4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]1-piperidinyl}anilino)sulfonyl]phenoxy}acetate;oooooo) methyl[4-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)phenoxy]acetate;pppppp)N-[5-({(2S)-3-[(1-{4-[(butylsulfonyl)amino]phenyl}-4-piperidinyl)amino]-2-hydroxypropyl}oxy)-2-hydroxyphenyl]benzenesulfonamide;qqqqqq)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(isopropylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butanesulfonamide;rrrrrr)4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]benzoicacid; ssssss) ethyl4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]benzoate;tttttt) methyl{4-[(4-{4-[((2R)-2-{4-chloro-3-[(methylsulfonyl)amino]phenyl)-2-hydroxyethyl)amino]-1-piperidinyl}anilino)sulfonyl]phenoxy}acetate;uuuuuu) methyl3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylate;vvvvvv)3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]-2-thiophenecarboxylicacid; wwwwww) benzyl[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]acetate;xxxxxx)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl)ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid; yyyyyy) benzyl[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]acetate;zzzzzz)[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)sulfonyl]aceticacid; aaaaaaa)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3-pyridinesulfonamide;bbbbbbb)3,4-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;ccccccc)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl)-4-(trifluoromethyl)benzenesulfonamide;ddddddd)N-}4-[4-(}(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-4-(trifluoromethoxy)benzenesulfonamide;eeeeeee)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-4-methoxybenzenesulfonamide;fffffff)4-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;ggggggg)4-butyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;hhhhhhh)3,5-dichloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;iiiiiii)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2,5-dimethoxybenzenesulfonamide;jjjjjjj)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-2,5-dimethoxybenzenesulfonamide;kkkkkkk) ethyl{[(4-butylphenyl)sulfonyl]-4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}acetate;lllllll)5-bromo-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide;mmmmmmm)5-bromo-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-methoxybenzenesulfonamide;nnnnnnn) ethyl([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;ooooooo) ethyl5-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-1H-indole-3-carboxylate;ppppppp) ethyl4-[((2S)-3-{[1-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-4-piperidinyl]amino}-2-hydroxypropyl)oxy]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate;qqqqqqq) benzyl((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;rrrrrrr)((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid; sssssss)([(3,4-dimethoxyphenyl)sulfonyl]-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)aceticacid; ttttttt) ethyl((butylsulfonyl)-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)acetate;uuuuuuu)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;vvvvvvv)N-{[5-({4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]anilino}sulfonyl)-2-thienyl]methyl}benzamide;wwwwwww)N-[(5-{[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;xxxxxxx)N-[(5-([4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)anilino]sulfonyl}-2-thienyl)methyl]benzamide;yyyyyyy)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;zzzzzzz)4-{[3-chloro-5-(trifluoromethyl)-2-pyridinyl]oxy}-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;aaaaaaaa)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;bbbbbbbb)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;cccccccc)3,5-dichloro-4-(2-chloro-4-nitrophenoxy)-N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;dddddddd)N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]-2-thiophenesulfonamide;eeeeeeee)4-butoxy-N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]benzenesulfonamide;ffffffff)N-[4-(4-{[(2S)-2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino-1-piperidinyl)phenyl]-2-thiophenesulfonamide;gggggggg)4-butoxy-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide;hhhhhhhh)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzenesulfonamide;iiiiiiii)N-[4-(4-{[(2S)-2-hydroxy-3-phenoxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;jjjjjjjj)N-[4-(4-{[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amino}-1-piperidinyl)phenyl]-3,4-dimethbxybenzenesulfonamide;kkkkkkkk)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-thiophenesulfonamide;llllllll) ethyl3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino)-1-piperidinyl}anilino)-3-oxopropanoate;mmmmmmmm)3-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid; nnnnnnnn) ethyl3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate;oooooooo)3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid; pppppppp) ethyl3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoate;qqqqqqqq)3-(cyclohexyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)-3-oxopropanoicacid; rrrrrrrr) ethyl{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate;ssssssss){[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}aceticacid; tttttttt) ethyl{[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}acetate;uuuuuuuu){[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}anilino)carbonyl]amino}aceticacid; vvvvvvvv)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-3,4-dimethoxybenzamide;wwwwwwww)2-chloro-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide;xxxxxxxx)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-2-(4-morpholinyl)acetamide;yyyyyyyy)2-(dimethylamino)-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}acetamide;zzzzzzzz)N-(4-{4-[(2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-dimethoxybenzamide;aaaaaaaaa)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl)amino)-1-piperidinyl]phenyl}butanamide;bbbbbbbbb)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]butanamide;ccccccccc)N-[4-(4-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzamide;ddddddddd)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-3,4-dimethoxybenzamide;eeeeeeeee)N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}-1,3-benzodioxole-5-carboxamide;fffffffff)N-[4-(4-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-piperidinyl)phenyl]-1,3-benzodioxole-5-carboxamide;ggggggggg)3-cyclopentyl-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]phenyl}propanamide;hhhhhhhhh)3-cyclopentyl-N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)propanamide;iiiiiiiii)N-(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1,3-benzodioxole-5-carboxamide;jjjjjjjjjj)N-acetyl-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]acetamide;kkkkkkkkk)4-butoxy-N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;lllllllll)N-[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;mmmmmmmmm)N-(4-{[4-(3-{[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamide;nnnnnnnnn)4-butoxy-N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]benzenesulfonamide;ooooooooo)N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]acetamide;ppppppppp)N-[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)phenyl]-3,4-dimethoxybenzenesulfonamide;or qqqqqqqqq)N-(4-{[4-(3-{[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxypropyl]amino}-1-azetidinyl)anilino]sulfonyl}phenyl)acetamideor a pharmaceutically acceptable salt thereof.
 4. A method of treatingmetabolic disorders mediated by insulin resistance or hyperglycemia in amammal in need thereof which comprises providing to said mammal, aneffective amount of a compound of formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and x² are each,independently, CO or SO₂, a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹²; and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with Ra11; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byR¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵;Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂-Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂-Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂—Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷;—COR¹⁷; —NR¹⁶SO₂R¹⁷; —NR¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted-by R¹⁶, OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10 ringatoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof.
 5. A method of treating or inhibiting type II diabetes ina mammal in need thereof which comprises providing to said mammal, aneffective amount of a compound of Formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of.1-6 carbon atoms per alkyl, moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byR¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵;Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂-Ar, or —NHSO₂—Het; or when R,¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷ or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷;—COR¹⁷; —NR¹⁶SO₂R¹⁷; —NR¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶ or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷isR¹⁶or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10 ringatoms, having 1-4 heteroatoms selected from oxygen, nitrogen; andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof.
 6. A method of modulating glucose levels in a mammal inneed thereof which comprises providing to said mammal, an effectiveamount of a compound of formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety,acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each; independently, NR⁶, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byby R¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted byR¹⁵; Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionallymono-, di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—OCO₂-alkyl of 1-6 carbon atoms, —CO₂-Ar, —CO₂-alkyl-Ar wherein thealkyl moiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂—Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷;—COR¹⁷; —NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹is (CH₂)_(m); T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atomsoptionally substituted with R¹¹, alkenyl of 2-7 carbon atoms optionallysubstituted with R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6carbon atoms, alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbonatoms per alkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkylmoiety, alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acylof 2-7 carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², andR³ are each, independently, hydrogen, alkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl,alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxyof 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6carbon atoms per alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of1-6 carbon atoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen,alkyl of 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbonatoms, alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbonatoms, carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7carbon atoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl -ester contains 1-6 carbon atoms;Y and Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹ cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; p1 R⁹ and R¹⁰ are each, independently, alkyl optionally substitutedby R¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted byR¹⁵; Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionallymono-, di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂-Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, -SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; CO₂R¹⁷; —OCOR¹⁷; NR¹⁶COR¹⁷; COR¹⁷;—NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof.
 7. A method of treating or inhibiting urinary incontinencein a mammal in need thereof which comprises providing to said mammal aneffective amount of a compound of formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹² and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byR¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵;Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂—Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷;—COR¹⁷; —NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n 1-3; or a pharmaceutically acceptablesalt thereof.
 8. A method of treating or inhibiting atherosclerosis,gastrointestinal disorders, neurogenetic inflammation, glaucoma, orocular hypertension in a mammal in nee thereof, which comprisesproviding to said mammal an effective amount of a compound of formula Ihaving the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbonatoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each; independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹ R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-1-6 carbon atoms; Het optionally substituted by R¹¹; R¹², or R¹³; orAr optionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byR¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵;Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂—Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, —SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷—CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷; —COR¹⁷;—NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or —NR16R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof.
 9. A method of increasing the lean meat to fat ratio in amammal in need thereof, which comprises providing to said mammal aneffective amount of a compound of formula I having the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R^(11;) R⁴ is hydrogen, alkylof 1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹² and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkynyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R^(11,) R¹², and R¹³; bicycloalkyl of₇-₁₁ carbon atoms optionally substituted by R11, R¹², and R¹³;—CO₂-alkyl of 1-6 carbon atoms; Het optionally substituted by R¹¹, R¹²,or R¹³; or Ar optionally substituted by R¹¹, R¹², and R¹³; or when R⁶and R⁷ are contained on a common nitrogen, they may be taken together toform a saturated 5-7 membered heterocycle that is optionally substitutedwith R¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionallysubstituted by R¹¹, R¹², and R¹³; Ar optionally mono-, di-, ortri-substituted by R¹⁵; Ar fused to a cycloalkyl ring of 3-8 carbonatoms, and optionally mono-, di-, or tri-substituted by R¹⁵; Hetoptionally mono-, di-, or tri-substituted by R¹⁵; R¹¹, R¹², or R¹³ areeach, independently, alkyl of 1-6 carbon atoms,, halogen, alkenyl of 2-7carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbonatoms, Ar-alkyl having 1-6 carbon atoms in the alkyl moiety, Aroptionally substituted with R¹⁴, Het optionally substituted with R¹⁴,hydroxy, alkoxy of 1-6 carbon atoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H,—OCO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbon atoms,—CO₂—Ar, —CO₂-alkyl-Ar wherein the alkyl moiety has 1-6 carbon atoms,—OCO₂—Ar, —CONH₂, —CONHOH, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 1-6 carbon atoms per alkyl moiety, —NHCONH-alkyl of 1-6carbon atoms, —NHSO₂-alkyl of 1-6 carbon atoms, —NHSO₂—Ar, or—NHSO₂—Het; or when R¹¹ and R¹² are contained on a common carbon atom ofan alkyl moiety, they may be taken together to form a spiro cycloalkylring of 3-8 carbon atoms; R¹⁴ is halogen, alkoxy of 1-6 carbon atoms,alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, hydroxy, acyl of 2-7 carbon atoms, —SO₂-alkyl of 1-6carbon atoms, —CO₂-alkyl of 1-6 carbon atoms, or alkoxycarbonylalkyl of3-13 carbon atoms; R¹⁵ is (a) hydroxy, halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶,—SR¹⁶, triflouromethyl, alkyl of 1-6 carbon atoms, —SO₂R¹⁷,—O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains 1-6 carbon atoms,—CO₂R¹⁷, —OCOR¹⁷, —NR¹⁶COR¹⁷; —COR¹⁷, —NR¹⁶SO₂R¹⁷; or —NR¹⁶CO₂R¹⁶; or(b) alkyl of 1-6 carbon atoms mono-, or di-substituted with hydroxy;halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl; alkyl of 1-6carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷; —COR¹⁷;—NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶, Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted R¹⁶, —OR¹⁶, —NR¹⁶,or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkylof 4-14 carbon atoms, benzyl, Ar or Het wherein the Ar or Het moietiesmay be optionally mono, di-, or tri- substituted with halogen, nitro,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, trifluoromethyl, alkyl of, 1-6 carbon atoms, alkoxy of 1-6carbon atoms, alkylthio of 1-6 carbon atoms; —CO₂H, —CO₂alkyl of 1-6carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ is R¹⁶ or —NR¹⁶R¹⁶;Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having1-4 heteroatoms selected from oxygen, nitrogen, sand sulfur; wherein theheterocycle may be saturated, unsaturated, or partially unsaturated; andmay be optionally fused to a phenyl ring; Ar is an aromatic ring systemcontaining 1-2 carbocyclic aromatic rings having 6-10 carbon atoms;m=1-3; n=1-3; or a pharmaceutically acceptable salt thereof.
 10. Apharmaceutical composition which comprises a compound of formula Ihaving the structure

wherein A is Ar or Het; X is —OCH₂—, —SCH₂—, or a bond; T¹ is (CH₂)_(m);T² is (CH₂)_(n); T is a bond, alkyl of 1-6 carbon atoms optionallysubstituted with R¹¹, alkenyl of 2-7 carbon atoms optionally substitutedwith R¹¹, alkynyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms,alkylamino of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms peralkyl moiety, alkylthioalkyl of 1-6 carbon atoms per alkyl moiety,alkoxy of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkylmoiety, alkyloxoalkyl of 1-6 carbon atoms per alkyl moiety, acyl of 2-7carbon atoms, or alkenylcarbonyl of 3-8 carbon atoms; R¹, R², and R³ areeach, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of3-8 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxy of 2-7 carbonatoms, cyano, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbonatoms, dialkylamino of 1-6 carbon atoms per alkyl group, formamido,ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbonatoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6 carbon atomsper alkyl group, dihydroxyphosphorylamino, —CO₂-alkyl of 1-6 carbonatoms, or Ar optionally substituted with R¹¹; R⁴ is hydrogen, alkyl of1-6 carbon atoms, halogen, hydroxy, alkyoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, amino, alkylamino of 1-6 carbon atoms,carboxy, acyl of 2-7 carbon atoms, ArCO—, alkoxycarbonyl of 2-7 carbonatoms, aminocarbonyl, alkylaminocarbonyl of 2-7 carbon atoms,alkylsulfonyl of 1-6 carbon atoms, or alkylsulfonylamino of 1-6 carbonatoms, R⁵ is

Aa is (i) an amino acid, wherein the nitrogen of amino acid attached tothe adjacent carbonyl of R⁵; or (ii) an alkyl ester of an amino acid,wherein the nitrogen of amino acid attached to the adjacent carbonyl ofR⁵, and the alkyl moiety of the alkyl ester contains 1-6 carbon atoms; Yand Z are each, independently, NR⁷, O, or S; X¹ and X² are each,independently, CO or SO₂; a dotted line represents and optional doublebond; R⁶, R⁷, and R⁸ are each, independently, hydrogen; alkyl of 1-6carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted by R¹¹, R¹², and R¹³; alkenyl of 2-7carbon atoms optionally substituted with R¹¹; cycloalkyl of 3-8 carbonatoms optionally substituted by R¹¹, R¹², and R¹³; bicycloalkyl of 7-11carbon atoms optionally substituted; by R¹¹, R¹², and R¹³; —CO₂-alkyl of1-6 carbon atoms; Het optionally substituted by R¹¹, R¹², or R¹³; or Aroptionally substituted by R¹¹, R¹², and R¹³; or when R⁶ and R⁷ arecontained on a common nitrogen, they may be taken together to form asaturated 5-7 membered heterocycle that is optionally substituted withR¹¹; R⁹ and R¹⁰ are each, independently, alkyl optionally substituted byR¹¹, R¹², and R¹³; Ar optionally mono-, di-, or tri-substituted by R¹⁵;Ar fused to a cycloalkyl ring of 3-8 carbon atoms, and optionally mono-,di-, or tri-substituted by R¹⁵; Het optionally mono-, di-, ortri-substituted by R¹⁵; R¹¹, R¹², or R¹³ are each, independently, alkylof 1-6 carbon atoms, halogen, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, Ar-alkyl having 1-6carbon atoms in the alkyl moiety, Ar optionally substituted with R¹⁴,Het optionally substituted with R¹⁴, hydroxy, alkoxy of 1-6 carbonatoms, Ar-oxy, oxo, —CN, —CHO, —CO₂H, —OCO₂-alkyl of 1-6 carbon atoms,—CO₂-alkyl of 1-6 carbon atoms, —CO₂—Ar, —CO₂-alkyl-Ar wherein the alkylmoiety has 1-6 carbon atoms, —OCO₂—Ar, —CONH₂, —CONHOH, amino,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl moiety, —NHCONH-alkyl of 1-6 carbon atoms, —NHSO₂-alkyl of 1-6carbon atoms, —NHSO₂—Ar, or —NHSO₂—Het; or when R¹¹ and R¹² arecontained on a common carbon atom of an alkyl moiety, they may be takentogether to form a spiro cycloalkyl ring of 3-8 carbon atoms; R¹⁴ ishalogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, hydroxy, acyl of 2-7carbon atoms, -SO₂-alkyl of 1-6 carbon atoms, —CO₂-alkyl of 1-6 carbonatoms, or alkoxycarbonylalkyl of 3-13 carbon atoms; R¹⁵ is (a) hydroxy,halogen, —CN, —NR¹⁶R¹⁶, —OR¹⁶, —SR¹⁶, triflouromethyl, alkyl of 1-6carbon atoms, —SO₂R¹⁷, —O-alkyl-CO₂R¹⁷ wherein the alkyl moiety contains1-6 carbon atoms, —CO₂R¹⁷, —OCOR¹⁷, -NR¹⁶COR¹⁷, —COR¹⁷, —NR¹⁶SO₂R¹⁷, or—NR¹⁶CO₂R¹⁶; or (b) alkyl of 1-6 carbon atoms mono-, or di-substitutedwith hydroxy; halogen; —CN; —NR¹⁶NR¹⁶; —OR¹⁶; —SR¹⁶; triflouromethyl;alkyl of 1-6 carbon atoms; —SO₂R¹⁷; —CO₂R¹⁷; —OCOR¹⁷; —NR¹⁶COR¹⁷;—COR¹⁷; —NR¹⁶SO₂R¹⁷; —NR¹⁶CO₂R¹⁶; Ar which may be optionally mono- ordi-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen; or Het which may beoptionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, or halogen;(c) Het optionally mono- or di-substituted by R¹⁶, —OR¹⁶, —NR¹⁶R¹⁶, orhalogen; or (d) Ar optionally mono- or di-substituted by R¹⁶, —OR¹⁶,—NR¹⁶R¹⁶, or halogen; R¹⁶ is hydrogen, alkyl of 1-6 carbon atoms,cycloalkylalkyl of 4-14 carbon atoms, benzyl, Ar or Het, wherein the Aror Het moieties may be optionally mono-, di-, or tri- substituted withhalogen, nitro, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl moiety, trifluoromethyl, alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, —CO₂H,—CO₂alkyl of 1-6 carbon atoms, or —SO₂alkyl of 1-6 carbon atoms; R¹⁷ isR¹⁶ or —NR¹⁶R¹⁶; Het is a monocyclic or bicyclic heterocycle of 5-10ring atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, andsulfur; wherein the heterocycle may be saturated, unsaturated, orpartially unsaturated; and may be optionally fused to a phenyl ring; Aris an aromatic ring system containing 1-2 carbocyclic aromatic ringshaving 6-10 carbon atoms; m=1-3; n=1-3; or a pharmaceutically acceptablesalt thereof, and a pharmaceutical carrier.